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  • 51. Cvetkovic, Jasmina Trifunovic
    et al.
    Wiklund, Per Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Medicin.
    Ahmed, Ejaz
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lefvert, Ann Kari
    Polymorphisms of IL-1beta, IL-1Ra, and TNF-alpha genes: A nested case-control study of their association with risk for stroke2005In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 14, no 1, p. 29-35Article in journal (Refereed)
    Abstract [en]

    Certain alleles of cytokine genes interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), and tumor necrosis factor alpha (TNF-α) are correlated with increased production of the proteins. The aim of this study was to investigate polymorphisms of these genes and their possible correlation with the development of stroke. This matched case-control study was nested within the population-based Västerbotten Intervention Program (VIP) cohort and the Northern Sweden World Health Organization MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases) cohort, based on individuals who were free from cardiovascular events when the cohorts were established. After an average period of 34.1 months, 113 individuals developed stroke and to each case 2 individuals not suffering from cardiovascular events were matched to serve as controls. Polymerase chain reaction amplification was used to analyze genetic polymorphisms. There was no association between polymorphic sites of the IL-1β and IL-1Ra genes and stroke. Carriage of haplotype A2+IL-1β/A2+IL-1Ra was significantly increased in normotensive cases (23.1%) compared with normotensive controls (8.9%) (odds ratio [OR] = 3.07; P = .045). In hypertensive male cases, there was an association between the A1A1 genotype of TNF-α and risk of stroke (OR = 2.46; P = .034). Our findings indicate an association between allele A1 of the TNF-α NcoI polymorphism and stroke in hypertensive male cases, as well as an association between haplotype A2+IL-1β/A2+IL-1Ra and stroke in normotensive cases.

  • 52. de Mello, Vanessa D.
    et al.
    Paananen, Jussi
    Lindström, Jaana
    Lankinen, Maria A.
    Shi, Lin
    Kuusisto, Johanna
    Pihlajamäki, Jussi
    Auriola, Seppo
    Lehtonen, Marko
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Nordin, Elise
    Ilanne-Parikka, Pirjo
    Keinänen-Kiukaanniemi, Sirkka
    Landberg, Rikard
    Eriksson, Johan G.
    Tuomilehto, Jaakko
    Hanhineva, Kati
    Uusitupa, Matti
    Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46337Article in journal (Refereed)
    Abstract [en]

    Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of alpha-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.

  • 53. Deloukas, Panos
    et al.
    Kanoni, Stavroula
    Willenborg, Christina
    Farrall, Martin
    Assimes, Themistocles L.
    Thompson, John R.
    Ingelsson, Erik
    Saleheen, Danish
    Erdmann, Jeanette
    Goldstein, Benjamin A.
    Stirrups, Kathleen
    Koenig, Inke R.
    Cazier, Jean-Baptiste
    Johansson, Asa
    Hall, Alistair S.
    Lee, Jong-Young
    Willer, Cristen J.
    Chambers, John C.
    Esko, Tonu
    Folkersen, Lasse
    Goel, Anuj
    Grundberg, Elin
    Havulinna, Aki S.
    Ho, Weang K.
    Hopewell, Jemma C.
    Eriksson, Niclas
    Kleber, Marcus E.
    Kristiansson, Kati
    Lundmark, Per
    Lyytikainen, Leo-Pekka
    Rafelt, Suzanne
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Strawbridge, Rona J.
    Thorleifsson, Gudmar
    Tikkanen, Emmi
    Van Zuydam, Natalie
    Voight, Benjamin F.
    Waite, Lindsay L.
    Zhang, Weihua
    Ziegler, Andreas
    Absher, Devin
    Altshuler, David
    Balmforth, Anthony J.
    Barroso, Ines
    Braund, Peter S.
    Burgdorf, Christof
    Claudi-Boehm, Simone
    Cox, David
    Dimitriou, Maria
    Do, Ron
    Doney, Alex S. F.
    El Mokhtari, NourEddine
    Eriksson, Per
    Fischer, Krista
    Fontanillas, Pierre
    Franco-Cereceda, Anders
    Gigante, Bruna
    Groop, Leif
    Gustafsson, Stefan
    Hager, Joerg
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Han, Bok-Ghee
    Hunt, Sarah E.
    Kang, Hyun M.
    Illig, Thomas
    Kessler, Thorsten
    Knowles, Joshua W.
    Kolovou, Genovefa
    Kuusisto, Johanna
    Langenberg, Claudia
    Langford, Cordelia
    Leander, Karin
    Lokki, Marja-Liisa
    Lundmark, Anders
    McCarthy, Mark I.
    Meisinger, Christa
    Melander, Olle
    Mihailov, Evelin
    Maouche, Seraya
    Morris, Andrew D.
    Mueller-Nurasyid, Martina
    Nikus, Kjell
    Peden, John F.
    Rayner, N. William
    Rasheed, Asif
    Rosinger, Silke
    Rubin, Diana
    Rumpf, Moritz P.
    Schaefer, Arne
    Sivananthan, Mohan
    Song, Ci
    Stewart, Alexandre F. R.
    Tan, Sian-Tsung
    Thorgeirsson, Gudmundur
    van der Schoot, C. Ellen
    Wagner, Peter J.
    Wells, George A.
    Wild, Philipp S.
    Yang, Tsun-Po
    Amouyel, Philippe
    Arveiler, Dominique
    Basart, Hanneke
    Boehnke, Michael
    Boerwinkle, Eric
    Brambilla, Paolo
    Cambien, Francois
    Cupples, Adrienne L.
    de Faire, Ulf
    Dehghan, Abbas
    Diemert, Patrick
    Epstein, Stephen E.
    Evans, Alun
    Ferrario, Marco M.
    Ferrieres, Jean
    Gauguier, Dominique
    Go, Alan S.
    Goodall, Alison H.
    Gudnason, Villi
    Hazen, Stanley L.
    Holm, Hilma
    Iribarren, Carlos
    Jang, Yangsoo
    Kahonen, Mika
    Kee, Frank
    Kim, Hyo-Soo
    Klopp, Norman
    Koenig, Wolfgang
    Kratzer, Wolfgang
    Kuulasmaa, Kari
    Laakso, Markku
    Laaksonen, Reijo
    Lee, Ji-Young
    Lind, Lars
    Ouwehand, Willem H.
    Parish, Sarah
    Park, Jeong E.
    Pedersen, Nancy L.
    Peters, Annette
    Quertermous, Thomas
    Rader, Daniel J.
    Salomaa, Veikko
    Schadt, Eric
    Shah, Svati H.
    Sinisalo, Juha
    Stark, Klaus
    Stefansson, Kari
    Tregouet, David-Alexandre
    Virtamo, Jarmo
    Wallentin, Lars
    Wareham, Nicholas
    Zimmermann, Martina E.
    Nieminen, Markku S.
    Hengstenberg, Christian
    Sandhu, Manjinder S.
    Pastinen, Tomi
    Syvanen, Ann-Christine
    Hovingh, G. Kees
    Dedoussis, George
    Franks, Paul W.
    Lehtimaki, Terho
    Metspalu, Andres
    Zalloua, Pierre A.
    Siegbahn, Agneta
    Schreiber, Stefan
    Ripatti, Samuli
    Blankenberg, Stefan S.
    Perola, Markus
    Clarke, Robert
    Boehm, Bernhard O.
    O'Donnell, Christopher
    Reilly, Muredach P.
    Maerz, Winfried
    Collins, Rory
    Kathiresan, Sekar
    Hamsten, Anders
    Kooner, Jaspal S.
    Thorsteinsdottir, Unnur
    Danesh, John
    Palmer, Colin N. A.
    Roberts, Robert
    Watkins, Hugh
    Schunkert, Heribert
    Samani, Nilesh J.
    Large-scale association analysis identifies new risk loci for coronary artery disease2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 1, p. 25-U52Article in journal (Refereed)
    Abstract [en]

    Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

  • 54. deSchoolmeester, J.
    et al.
    Palming, J.
    Persson, T.
    Pereira, M. J.
    Wallerstedt, E.
    Brown, H.
    Gill, D.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, M. K.
    Rees, A.
    Eriksson, J. W.
    Differences between men and women in the regulation of adipose 11 beta-HSD1 and in its association with adiposity and insulin resistance2013In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, no 11, p. 1056-1060Article in journal (Refereed)
    Abstract [en]

    This study explored sex differences in 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 +/- 15.3years, body mass index (BMI) 27.2 +/- 3.9kg/m(2)]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11-HSD1 mRNA expression. This study suggests that there are sex differences in 11-HSD1 regulation and in its associations with markers of obesity and IR.

  • 55. Ding, Ming
    et al.
    Huang, Tao
    Bergholdt, Helle K. M.
    Nordestgaard, Borge G.
    Ellervik, Christina
    Qi, Lu
    Frazier-Wood, Alexis C.
    Aslibekyan, Stella
    North, Kari E.
    Voortman, Trudy
    Graff, Mariaelisa
    Smith, Caren E.
    Lai, Chao-Qiang
    Varbo, Anette
    Lemaitre, Rozenn N.
    de Jonge, Ester A. L.
    Fumeron, Frederic
    Corella, Dolores
    Wang, Carol A.
    Tjonneland, Anne
    Overvad, Kim
    Sorensen, Thorkild I. A.
    Feitosa, Mary F.
    Wojczynski, Mary K.
    Kahonen, Mika
    Ahmad, Shafqat
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Psaty, Bruce M.
    Siscovick, David S.
    Barroso, Ines
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hernandez, Dena
    Ferrucci, Luigi
    Bandinelli, Stefania
    Linneberg, Allan
    Sandholt, Camilla Helene
    Pedersen, Oluf
    Hansen, Torben
    Schulz, Christina-Alexandra
    Sonestedt, Emily
    Orho-Melander, Marju
    Chen, Tzu-An
    Rotter, Jerome I.
    Allison, Mathew A.
    Rich, Stephen S.
    Sorli, Jose V.
    Coltell, Oscar
    Pennell, Craig E.
    Eastwood, Peter R.
    Hofman, Albert
    Uitterlinden, Andre G.
    Zillikens, MCarola
    van Rooij, Frank J. A.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ridker, Paul M.
    Viikari, Jorma
    Raitakari, Olli
    Lehtimaki, Terho
    Mikkila, Vera
    Willett, Walter C.
    Wang, Yujie
    Tucker, Katherine L.
    Ordovas, Jose M.
    Kilpelainen, Tuomas O.
    Province, Michael A.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA; Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Arnett, Donna K.
    Tanaka, Toshiko
    Toft, Ulla
    Ericso, Ulrika
    Franco, Oscar H.
    Mozaffarian, Dariush
    Hu, Frank B.
    Chasman, Daniel I.
    Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study2017In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 356, article id j1000Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. DESIGN Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable. SETTING CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. PARTICIPANTS Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis. MAIN OUTCOME MEASURES The instrumental variable estimation was conducted using the ratio of coefficients approach. Using metaanalysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized. RESULTS Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (beta=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: beta=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11). CONCLUSION The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

  • 56. Duell, Eric J
    et al.
    Bonet, Catalina
    Muñoz, Xavier
    Lujan-Barroso, Leila
    Weiderpass, Elisabete
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Severi, Gianluca
    Canzian, Federico
    Rizzato, Cosmeri
    Boeing, Heiner
    Overvad, Kim
    Tjønneland, Anne
    Argüelles, Marcial
    Sánchez-Cantalejo, Emilio
    Chamosa, Saioa
    Huerta, José María
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Rutch C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Yiannakouris, Nikos
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Bueno-de-Mesquita, H B As
    Siersema, Peter D
    Peeters, Petra H M
    Ohlsson, Bodil
    Lindkvist, Björn
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Matthias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Fenger, Claus
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. 880-893Article in journal (Refereed)
    Abstract [en]

    ABO blood serotype A is known to be associated with risk of gastric cancer (GC), but little is known how ABO alleles and the fucosyltransferase (FUT) enzymes and genes which are involved in Lewis antigen formation [and in Helicobacter pylori (H. pylori) binding and pathogenicity] may be related to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group A (AO+AA, odds ratio = 1.84, 95%CI = 1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes) in FUT2 (Se), FUT3 (Le) and FUT6 with intestinal-type GC. Further, one variant in ABO, two in FUT3 and two in FUT6 were associated with H. pylori infection status in controls, and two of these (in FUT3 and FUT6) were weakly associated with intestinal-type GC risk. None of the individual variants surpassed a Bonferroni corrected p-value cutoff of 0.0016; however, after a gene-based permutation test, two loci [FUT3(Le)/FUT5/FUT6 and FUT2(Se)] were significantly associated with diffuse- and intestinal-type GC, respectively. Replication and functional studies are therefore recommended to clarify the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis.

  • 57. Duell, Eric J
    et al.
    Lujan-Barroso, Leila
    Llivina, Claudia
    Muñoz, Xavier
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Boeing, Heiner
    Buijsse, Brian
    Canzian, Federico
    Johnson, Theron
    Dalgård, Christine
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Sánchez, Soledad C
    Sánchez-Cantalejo, Emilio
    Huerta, José-María
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Travis, Ruth C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Rafnsson, Snorri
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Grioni, Sara
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra H
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skeie, Guri
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort2013In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.

  • 58. Duell, Eric J.
    et al.
    Travier, Noemie
    Lujan-Barroso, Leila
    Dossus, Laure
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Tumino, Rosario
    Masala, Giovanna
    Krogh, Vittorio
    Panico, Salvatore
    Ricceri, Fulvio
    Luisa Redondo, Maria
    Dorronsoro, Miren
    Molina-Montes, Esther
    Huerta, Jose M.
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick J.
    Allen, Naomi E.
    Travis, Ruth
    Siersema, Peter D.
    Peeters, Petra H. M.
    Trichopoulou, Antonia
    Fragogeorgi, Eirini
    Oikonomou, Eleni
    Boeing, Heiner
    Schuetze, Madlen
    Canzian, Federico
    Lukanova, Annekatrin
    Tjonneland, Anne
    Roswall, Nina
    Overvad, Kim
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Lund, Eiliv
    Lindkvist, Bjorn
    Johansen, Dorthe
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Fedirko, Veronika
    Jenab, Mazda
    Michaud, Dominique S.
    Riboli, Elio
    Bueno-de-Mesquita, H. Bas
    Menstrual and reproductive factors in women, genetic variation in CYP17A1, and pancreatic cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 9, p. 2164-2175Article in journal (Refereed)
    Abstract [en]

    Menstrual and reproductive factors and exogenous hormone use have been investigated as pancreatic cancer risk factors in case-control and cohort studies, but results have been inconsistent. We conducted a prospective examination of menstrual and reproductive factors, exogenous hormone use and pancreatic cancer risk (based on 304 cases) in 328,610 women from the EPIC cohort. Then, in a case-control study nested within the EPIC cohort, we examined 12 single nucleotide polymorphisms (SNPs) in CYP17A1 (an essential gene in sex steroid metabolism) for association with pancreatic cancer in women and men (324 cases and 353 controls). Of all factors analyzed, only younger age at menarche (<12 vs. 13 years) was moderately associated with an increased risk of pancreatic cancer in the full cohort; however, this result was marginally significant (HR = 1.44; 95% CI = 0.992.10). CYP17A1 rs619824 was associated with HRT use (p value = 0.037) in control women; however, none of the SNPs alone, in combination, or as haplotypes were associated with pancreatic cancer risk. In conclusion, with the possible exception of an early age of menarche, none of the menstrual and reproductive factors, and none of the 12 common genetic variants we evaluated at the CYP17A1 locus makes a substantial contribution to pancreatic cancer susceptibility in the EPIC cohort.

  • 59. Ehret, Georg B.
    et al.
    Ferreira, Teresa
    Chasman, Daniel I.
    Jackson, Anne U.
    Schmidt, Ellen M.
    Johnson, Toby
    Thorleifsson, Gudmar
    Luan, Jian'an
    Donnelly, Louise A.
    Kanoni, Stavroula
    Petersen, Ann -Kristin
    Pihurl, Vasyl
    Strawbridge, Rona J.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Hughes, Maria F.
    Meirelles, Osorio
    Kaakinen, Marika
    Bouatia-Naji, Nabila
    Kristiansson, Kati
    Shah, Sonia
    Kleber, Marcus E.
    Guo, Xiuqing
    Lyytikainen, Leo-Pekka
    Fava, Cristiano
    Eriksson, Nidas
    Nolte, Ilja M.
    Magnusson, Patrik K.
    Salfati, Elias L.
    Rallidis, Loukianos S.
    Theusch, Elizabeth
    Smith, Andrew J. P.
    Folkersen, Lasse
    Witkowska, Kate
    Pers, Tune H.
    Joehanes, Roby
    Kim, Stuart K.
    Lataniotis, Lazaros
    Jansen, Rick
    Johnson, Andrew D.
    Warren, Helen
    Kim, Young Jin
    Zhao, Wei
    Wu, Ying
    Tayo, Bamidele O.
    Bochud, Murielle
    Absher, Devin
    Adair, Linda S.
    Amin, Najaf
    Arkingl, Dan E.
    Axelsson, Tomas
    Baldassarre, Damian
    Balkau, Beverley
    Bandinelli, Stefania
    Barnes, Michael R.
    Barroso, Ines
    Bevan, Stephen
    Bis, Joshua C.
    Bjornsdottir, Gyda
    Boehnke, Michael
    Boerwinkle, Eric
    Bonnycastle, Lori L.
    Boomsma, Dorret I.
    Bornstein, Stefan R.
    Brown, Morris J.
    Burnier, Michel
    Cabrera, Claudia P.
    Chambers, John C.
    Chang, I-Shou
    Cheng, Ching-Yu
    Chines, Peter S.
    Chung, Ren-Hua
    Collins, Francis S.
    Connell, John M.
    Doring, Angela
    Dallongeville, Jean
    Danesh, John
    de Faire, Ulf
    Delgado, Graciela
    Dominiczak, Anna F.
    Doney, Alex S. F.
    Drenos, Fotios
    Edkins, Sarah
    Eicher, John D.
    Elosua, Roberto
    Enroth, Stefan
    Erdmann, Jeanette
    Eriksson, Per
    Esko, Tonu
    Evangelou, Evangelos
    Evans, Alun
    Fai, Tove
    Farra, Martin
    Felixl, Janine F.
    Ferrieres, Jean
    Ferrucci, Luigi
    Fornage, Myriam
    Forrester, Terrence
    Franceschinil, Nora
    Franco, Oscar H.
    Franco-Cereceda, Anders
    Fraser, Ross M.
    Ganesh, Santhi K.
    Gao, He
    Gertow, Karl
    Gianfagna, Francesco
    Gigante, Bruna
    Giulianini, Franco
    Goe, Anuj
    Goodall, Alison H.
    Goodarzi, Mark
    Gorski, Mathias
    Grassler, Jurgen
    Groves, Christopher J.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hartikainen, Anna-Liisa
    Hassinen, Maija
    Havulinna, Aki S.
    Hayward, Caroline
    Hercberg, Serge
    Herzig, Karl-Heinz
    Hicks, Andrew A.
    Hingorani, Aroon D.
    Hirschhorn, Joel N.
    Hofmanl, Albert
    Holmen, Jostein
    Holmen, Oddgeir Lingaas
    Hottenga, Jouke-Jan
    Howard, Phil
    Hsiung, Chao A.
    Hunt, Steven C.
    Ikram, M. Arfan
    Illig, Thomas
    Iribarren, Carlos
    Jensen, Richard A.
    Kahonen, Mika
    Kang, Hyun Min
    Kathiresan, Sekar
    Keating, Brendan J.
    Khaw, Kay-Tee
    Kim, Yun Kyoung
    Kim, Eric
    Kivimaki, Mika
    Klopp, Norman
    Kolovou, Genovefa
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kosova, Gulum
    Krauss, Ronald M.
    Kuh, Diana
    Kutalik, Zoltan
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Lakka, Timo A.
    Lee, Nanette R.
    Lee, I-Te
    Lee, Wen-Jane
    Levy, Daniel
    Li, Xiaohui
    Liang, Kae-Woei
    Lin, Honghuang
    Lin, Li
    Lindstrom, Jaana
    Lobbens, Stephane
    Mannisto, Satu
    Muller, Gabriele
    Muller-Nurasyid, Martina
    Mach, Francois
    Markus, Hugh S.
    Marouli, Eirini
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Menni, Cristina
    Metspalu, Andres
    Mijatovic, Vladan
    Moilanen, Leena
    Montasser, May E.
    Morris, Andrew D.
    Morrison, Alanna C.
    Mulas, Antonella
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nikus, Kjell
    O'Donnell, Christopher J.
    O'Reilly, Paul F.
    Ong, Ken K.
    Paccaud, Fred
    Palmer, Cameron D.
    Parsa, Afshin
    Pedersen, Nancy L.
    Penninx, Brenda W.
    Perola, Markus
    Peters, Annette
    Poulter, Neil
    Pramstaller, Peter P.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rao, Dabeeru C.
    Rasheed, Asif
    Rayner, N. William
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rettig, Rainer
    Rice, Kenneth M.
    Roberts, Robert
    Rose, Lynda M.
    Rossouw, Jacques
    Samani, Nilesh J.
    Sanna, Serena
    Saramies, Jouko
    Schunkert, Heribert
    Sebert, Sylvain
    Sheu, Wayne H-H
    Shin, Young-Ah
    Sim, Xueling
    Smit, Johannes H.
    Smith, Albert V.
    Sosa, Maria X.
    Spector, Tim D.
    Stancakova, Alena
    Stanton, Alice V.
    Stirrups, Kathleen E.
    Stringham, Heather M.
    Sundstrom, Johan
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tai, E-Shyong
    Tanaka, Toshiko
    Tarasov, Kirill V.
    Teumer, Alexander
    Thorsteinsdottir, Unnur
    Tobin, Martin D.
    Tremoli, Elena
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Vaez, Ahmad
    Vaidya, Dhananjay
    van Duijn, Cornelia M.
    van Iperen, Erik P. A.
    Vasan, Ramachandran S.
    Verwoert, Germaine C.
    Virtamo, Jarmo
    Vitart, Veronique
    Voight, Benjamin F.
    Vollenweider, Peter
    Wagner, Aline
    Wain, Louise V.
    Wareham, Nicholas J.
    Watldns, Hugh
    Weder, Alan B.
    Westra, Harm Jan
    Wilks, Rainford
    Wilsgaard, Tom
    Wilson, James F.
    Wong, Tien Y.
    Yang, Tsun-Po
    Yao, Jie
    Yengo, Loic
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Xiaofeng
    Bovet, Pascal
    Cooper, Richard S.
    Mohlke, Karen L.
    Saleheen, Danish
    Lee, Jong-Young
    Elliott, Paul
    Gierman, Hinco J.
    Willer, Cristen J.
    Franke, Lude
    Hovingh, G. Kees
    Taylor, Kent D.
    Dedoussis, George
    Sever, Peter
    Wong, Andrew
    Lind, Lars
    Assimes, Themistocles L.
    Njolstad, Inger
    Schwarz, Peter E. H.
    Langenberg, Claudia
    Snieder, Harold
    Caulfield, Mark J.
    Melander, E.
    Laakso, Markku
    Saltevo, Juha
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Ingelsson, Erik
    Lehtimaki, Terho
    Hveem, Kristian
    Palmas, Walter
    Marz, Winfried
    Kumar, Meena
    Salomaa, Veikko
    Chen, Yii-Der I.
    Rotter, Jerome I.
    Froguel, Philippe
    Jarvelin, Marjo-Riitta
    Lakatta, Edward G.
    Kuulasmaa, Kari
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
    Hamsten, Anders
    Wichmann, H-Erich
    Palmer, Colin N. A.
    Stefansson, Kari
    Ridker, Paul M.
    Loos, Ruth J. F.
    Chalcravarti, Aravinda
    Deloukas, Panos
    Morris, Andrew P.
    Newton-Cheh, Christopher
    Munroe, Patricia B.
    The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1171-1184Article in journal (Refereed)
    Abstract [en]

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

  • 60. Ek, Weronica E.
    et al.
    Tobi, Elmar W.
    Ahsan, Muhammad
    Lampa, Erik
    Ponzi, Erica
    Kyrtopoulos, Soterios A.
    Georgiadis, Panagiotis
    Lumey, L. H.
    Heijmans, Bastiaan T.
    Botsivali, Maria
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Karlsson, Torgny
    Rask-Andersen, Mathias
    Palli, Domenico
    Ingelsson, Erik
    Hedman, Åsa K.
    Nilsson, Lena M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vineis, Paolo
    Lind, Lars
    Flanagan, James M.
    Johansson, Åsa
    Tea and coffee consumption in relation to DNA methylation in four European cohorts2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal (Refereed)
    Abstract [en]

    Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

  • 61. Elena, J. W.
    et al.
    Steplowski, E.
    Yu, K.
    Hartge, P.
    Tobias, G. S.
    Brotzman, M. J.
    Chanock, S. J.
    Stolzenberg-Solomon, R. Z.
    Arslan, A. A.
    Bueno-De-Mesquita, H. B.
    Helzlsouer, K.
    Jacobs, E. J.
    Lacroix, A.
    Petersen, G.
    Zheng, W.
    Albanes, D.
    Allen, N. E.
    Amundadottir, L.
    Bao, Y.
    Boeing, H.
    Boutron-Ruault, M. -C
    Buring, J. E.
    Gaziano, J. M.
    Giovannucci, E. L.
    Duell, E. J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Howard, B. V.
    Hunter, D. J.
    Hutchinson, A.
    Jacobs, K. B.
    Kooperberg, C.
    Kraft, P.
    Mendelsohn, J. B.
    Michaud, D. S.
    Palli, D.
    Phillips, L. S.
    Overvad, K.
    Patel, A. V.
    Sansbury, L.
    Shu, X. -O
    Simon, M. S.
    Slimani, N.
    Trichopoulos, D.
    Visvanathan, K.
    Virtamo, J.
    Wolpin, B. M.
    Zeleniuch-Jacquotte, A.
    Fuchs, C. S.
    Hoover, R. N.
    Gross, M.
    Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 1, p. 13-25Article in journal (Refereed)
    Abstract [en]

    Purpose: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). Methods: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Results: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). Conclusions: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.

  • 62. Eliassen, A. Heather
    et al.
    Hendrickson, Sara J.
    Brinton, Louise A.
    Buring, Julie E.
    Campos, Hannia
    Dai, Qi
    Dorgan, Joanne F.
    Franke, Adrian A.
    Gao, Yu-tang
    Goodman, Marc T.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Helzlsouer, Kathy J.
    Hoffman-Bolton, Judy
    Hulten, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sesso, Howard D.
    Sowell, Anne L.
    Tamimi, Rulla M.
    Toniolo, Paolo
    Wilkens, Lynne R.
    Winkvist, Anna
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Hankinson, Susan E.
    Circulating Carotenoids and Risk of Breast Cancer: Pooled Analysis of Eight Prospective Studies2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 24, p. 1905-1916Article in journal (Refereed)
    Abstract [en]

    Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Statistically significant inverse associations with breast cancer were observed for -carotene (top vs bottom quintile RR 0.87, 95% CI 0.71 to 1.05, Ptrend .04), -carotene (RR 0.83, 95% CI 0.70 to 0.98, Ptrend .02), luteinzeaxanthin (RR 0.84, 95% CI 0.70 to 1.01, Ptrend .05), lycopene (RR 0.78, 95% CI 0.62 to 0.99, Ptrend .02), and total carotenoids (RR 0.81, 95% CI 0.68 to 0.96, Ptrend .01). -Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER) than for ER tumors (eg, -carotene: ER: top vs bottom quintile RR 0.52, 95% CI 0.36 to 0.77, Ptrend .001; ER: RR 0.83, 95% CI 0.66 to 1.04, Ptrend .06; Pheterogeneity .01). This comprehensive prospective analysis suggests women with higher circulating levels of -carotene, -carotene, luteinzeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer. 

  • 63.
    Englund, Undis
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nilsson, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Pettersson Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Active commuting reduces the risk of wrist fractures in middle-aged women: the UFO study2013In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, no 2, p. 533-540Article in journal (Refereed)
    Abstract [en]

    Middle-aged women with active commuting had significantly lower risk for wrist fracture than women commuting by car/bus.

    INTRODUCTION: Our purpose was to investigate whether a physically active lifestyle in middle-aged women was associated with a reduced risk of later sustaining a low-trauma wrist fracture.

    METHODS: The Umeå Fracture and Osteoporosis (UFO) study is a population-based nested case-control study investigating associations between lifestyle and fragility fractures. From a cohort of ~35,000 subjects, we identified 376 female wrist fracture cases who had reported data regarding their commuting habits, occupational, and leisure physical activity, before they sustained their fracture. Each fracture case was compared with at least one control drawn from the same cohort and matched for age and week of reporting data, yielding a total of 778 subjects. Mean age at baseline was 54.3 ± 5.8 years, and mean age at fracture was 60.3 ± 5.8 years.

    RESULTS: Conditional logistic regression analysis with adjustments for height, body mass index, smoking, and menopausal status showed that subjects with active commuting (especially walking) were at significantly lower risk of sustaining a wrist fracture (OR 0.48; 95 % CI 0.27-0.88) compared with those who commuted by car or bus. Leisure time activities such as dancing and snow shoveling were also associated with a lower fracture risk, whereas occupational activity, training, and leisure walking or cycling were unrelated to fracture risk.

    CONCLUSION: This study suggests that active commuting is associated with a lower wrist fracture risk, in middle-aged women.

  • 64. Erzurumluoglu, A Mesut
    et al.
    Liu, Mengzhen
    Jackson, Victoria E
    Barnes, Daniel R
    Datta, Gargi
    Melbourne, Carl A
    Young, Robin
    Batini, Chiara
    Surendran, Praveen
    Jiang, Tao
    Adnan, Sheikh Daud
    Afaq, Saima
    Agrawal, Arpana
    Altmaier, Elisabeth
    Antoniou, Antonis C
    Asselbergs, Folkert W
    Baumbach, Clemens
    Bierut, Laura
    Bertelsen, Sarah
    Boehnke, Michael
    Bots, Michiel L
    Brazel, David M
    Chambers, John C
    Chang-Claude, Jenny
    Chen, Chu
    Corley, Janie
    Chou, Yi-Ling
    David, Sean P
    de Boer, Rudolf A
    de Leeuw, Christiaan A
    Dennis, Joe G
    Dominiczak, Anna F
    Dunning, Alison M
    Easton, Douglas F
    Eaton, Charles
    Elliott, Paul
    Evangelou, Evangelos
    Faul, Jessica D
    Foroud, Tatiana
    Goate, Alison
    Gong, Jian
    Grabe, Hans J
    Haessler, Jeff
    Haiman, Christopher
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hammerschlag, Anke R
    Harris, Sarah E
    Hattersley, Andrew
    Heath, Andrew
    Hsu, Chris
    Iacono, William G
    Kanoni, Stavroula
    Kapoor, Manav
    Kaprio, Jaakko
    Kardia, Sharon L
    Karpe, Fredrik
    Kontto, Jukka
    Kooner, Jaspal S
    Kooperberg, Charles
    Kuulasmaa, Kari
    Laakso, Markku
    Lai, Dongbing
    Langenberg, Claudia
    Le, Nhung
    Lettre, Guillaume
    Loukola, Anu
    Luan, Jian'an
    Madden, Pamela A F
    Mangino, Massimo
    Marioni, Riccardo E
    Marouli, Eirini
    Marten, Jonathan
    Martin, Nicholas G
    McGue, Matt
    Michailidou, Kyriaki
    Mihailov, Evelin
    Moayyeri, Alireza
    Moitry, Marie
    Müller-Nurasyid, Martina
    Naheed, Aliya
    Nauck, Matthias
    Neville, Matthew J
    Nielsen, Sune Fallgaard
    North, Kari
    Perola, Markus
    Pharoah, Paul D P
    Pistis, Giorgio
    Polderman, Tinca J
    Posthuma, Danielle
    Poulter, Neil
    Qaiser, Beenish
    Rasheed, Asif
    Reiner, Alex
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Lund University.
    Rice, John
    Rohde, Rebecca
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Samani, Nilesh J
    Samuel, Maria
    Schlessinger, David
    Scholte, Steven H
    Scott, Robert A
    Sever, Peter
    Shao, Yaming
    Shrine, Nick
    Smith, Jennifer A
    Starr, John M
    Stirrups, Kathleen
    Stram, Danielle
    Stringham, Heather M
    Tachmazidou, Ioanna
    Tardif, Jean-Claude
    Thompson, Deborah J
    Tindle, Hilary A
    Tragante, Vinicius
    Trompet, Stella
    Turcot, Valerie
    Tyrrell, Jessica
    Vaartjes, Ilonca
    van der Leij, Andries R
    van der Meer, Peter
    Varga, Tibor V
    Verweij, Niek
    Völzke, Henry
    Wareham, Nicholas J
    Warren, Helen R
    Weir, David R
    Weiss, Stefan
    Wetherill, Leah
    Yaghootkar, Hanieh
    Yavas, Ersin
    Jiang, Yu
    Chen, Fang
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Wei
    Zhao, Wei
    Zhou, Kaixin
    Amouyel, Philippe
    Blankenberg, Stefan
    Caulfield, Mark J
    Chowdhury, Rajiv
    Cucca, Francesco
    Deary, Ian J
    Deloukas, Panos
    Di Angelantonio, Emanuele
    Ferrario, Marco
    Ferrières, Jean
    Franks, Paul W
    Frayling, Tim M
    Frossard, Philippe
    Hall, Ian P
    Hayward, Caroline
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden..
    Jukema, J Wouter
    Kee, Frank
    Männistö, Satu
    Metspalu, Andres
    Munroe, Patricia B
    Nordestgaard, Børge Grønne
    Palmer, Colin N A
    Salomaa, Veikko
    Sattar, Naveed
    Spector, Timothy
    Strachan, David Peter
    van der Harst, Pim
    Zeggini, Eleftheria
    Saleheen, Danish
    Butterworth, Adam S
    Wain, Louise V
    Abecasis, Goncalo R
    Danesh, John
    Tobin, Martin D
    Vrieze, Scott
    Liu, Dajiang J
    Howson, Joanna M M
    Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci2019In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed)
    Abstract [en]

    Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

  • 65. Espinosa-Parrilla, Yolanda
    et al.
    Munoz, Xavier
    Bonet, Catalina
    Garcia, Nadia
    Vencesla, Adoracion
    Yiannakouris, Nikos
    Naccarati, Alessio
    Sieri, Sabina
    Panico, Salvatore
    Huerta, Jose M.
    Barricarte, Aurelio
    Menendez, Virginia
    Sanchez-Cantalejo, Emilio
    Dorronsoro, Miren
    Brennan, Paul
    Duarte-Salles, Talita
    Bueno-de-Mesquita, H. B. (As)
    Weiderpass, Elisabete
    Lund, Eiliv
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Numans, Mattijs E.
    Tumino, Rosario
    Canzian, Federico
    Campa, Daniele
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Ohlsson, Bodil
    Lindkvist, Bjorn
    Overvad, Kim
    Tjonneland, Anne
    Palli, Domenico
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nick
    Boeing, Heiner
    Nesi, Gabriella
    Riboli, Elio
    Gonzalez, Carlos A.
    Sala, Nuria
    Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 9, p. 2065-2076Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value=1.7 x 10(-4); odds ratio, OR=1.72; 95% confidence interval, CI=1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value=5.38 x 10(-3); OR=0.56, 95% CI=0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value=5.40 x 10(-3); OR=1.41, 95% CI=1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

  • 66. Espín-Pérez, Almudena
    et al.
    Hebels, Dennie G. A. J.
    Kiviranta, Hannu
    Rantakokko, Panu
    Georgiadis, Panagiotis
    Botsivali, Maria
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palli, Domenico
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Chadeau-Hyam, Marc
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C. S.
    de Kok, Theo M. C. M.
    Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs)2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 746Article in journal (Refereed)
    Abstract [en]

    PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.

  • 67. Fages, Anne
    et al.
    Ferrari, Pietro
    Monni, Stefano
    Dossus, Laure
    Floegel, Anna
    Mode, Nicolle
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, Lyon, France .
    Travis, Ruth C.
    Bamia, Christina
    Sánchez-Pérez, María-José
    Chiodini, Paolo
    Boshuizen, Hendriek C.
    Chadeau-Hyam, Marc
    Riboli, Elio
    Jenab, Mazda
    Elena-Herrmann, Bénédicte
    Investigating sources of variability in metabolomic data in the EPIC study: the Principal Component Partial R-square (PC-PR2) method2014In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 10, no 6, p. 1074-1083Article in journal (Refereed)
    Abstract [en]

    The key goal of metabolomic studies is to identify relevant individual biomarkers or composite metabolic patterns associated with particular disease status or patho-physiological conditions. There are currently very few approaches to evaluate the variability of metabolomic data in terms of characteristics of individuals or aspects pertaining to technical processing. To address this issue, a method was developed to identify and quantify the contribution of relevant sources of variation in metabolomic data prior to investigation of etiological hypotheses. The Principal Component Partial R-square (PC-PR2) method combines features of principal component and of multivariable linear regression analyses. Within the European Prospective Investigation into Cancer and nutrition (EPIC), metabolic profiles were determined by H-1 NMR analysis on 807 serum samples originating from a nested liver cancer case-control study. PC-PR2 was used to quantify the variability of metabolomic profiles in terms of study subjects age, sex, body mass index, country of origin, smoking status, diabetes and fasting status, as well as factors related to sample processing. PC-PR2 enables the evaluation of important sources of variations in metabolomic studies within large-scale epidemiological investigations.

  • 68. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 10192Article in journal (Refereed)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 69. Fehringer, Gordon
    et al.
    Kraft, Peter
    Pharoah, Paul D P
    Eeles, Rosalind A
    Chatterjee, Nilanjan
    Schumacher, Fredrick R
    Schildkraut, Joellen M
    Lindstrom, Sara
    Brennan, Paul
    Bickeböller, Heike
    Houlston, Richard S
    Landi, Maria Teresa
    Caporaso, Neil E
    Risch, Angela
    Amin Al Olama, Ali
    Berndt, Sonja I
    Giovannucci, Edward
    Gronberg, Henrik
    Kote-Jarai, Zsofia
    Ma, Jing
    Muir, Kenneth
    Stampfer, Meir J
    Stevens, Victoria L
    Wiklund, Fredrik
    Willett, Walter C
    Goode, Ellen L
    Permuth, Jennifer B
    Risch, Harvey A
    Reid, Brett M
    Bezieau, Stéphane
    Brenner, Hermann
    Chan, Andrew T
    Chang-Claude, Jenny
    Hudson, Thomas J
    Kocarnik, Jonathan
    Newcomb, Polly A
    Schoen, Robert E
    Slattery, Martha L
    White, Emily
    Adank, Muriel A
    Ahsan, Habibul
    Aittomaki, Kristiina
    Baglietto, Laura
    Blomquist, Carl
    Canzian, Federico
    Czene, Kamila
    Dos Santos Silva, Isabel
    Eliassen, A Heather
    Figueroa, Jonine D
    Flesch-Janys, Dieter
    Fletcher, Olivia
    Garcia-Closas, Montserrat
    Gaudet, Mia M
    Johnson, Nichola
    Hall, Per
    Hazra, Aditi
    Hein, Rebecca
    Hofman, Albert
    Hopper, John L
    Irwanto, Astrid
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Kaaks, Rudolf
    Kibriya, Muhammad G
    Lichtner, Peter
    Liu, Jian-Jun
    Lund, Eiliv
    Makalic, Enes
    Meindl, Alfons
    Müller-Myhsok, Bertram
    Muranen, Taru A
    Nevanlinna, Heli
    Peeters, Petra H
    Peto, Julian
    Prentice, Ross L
    Rahman, Nazneen
    Sanchez, Maria-Jose
    Schmidt, Daniel F
    Schmutzler, Rita K
    Southey, Melissa C
    Tamimi, Rulla M
    Travis, Ruth C
    Turnbull, Clare
    Uitterlinden, Andre G
    Wang, Zhaoming
    Whittemore, Alice S
    Yang, Xiaohong R
    Zheng, Wei
    Rafnar, Thorunn
    Gudmundsson, Julius
    Stacey, Simon N
    Stefansson, Kari
    Sulem, Patrick
    Chen, Y Ann
    Tyrer, Jonathan P
    Christiani, David C
    Wei, Yongyue
    Shen, Hongbing
    Hu, Zhibin
    Shu, Xiao-Ou
    Shiraishi, Kouya
    Takahashi, Atsushi
    Bossé, Yohan
    Obeidat, Ma'en
    Nickle, David
    Timens, Wim
    Freedman, Matthew L
    Li, Qiyuan
    Seminara, Daniela
    Chanock, Stephen J
    Gong, Jian
    Peters, Ulrike
    Gruber, Stephen B
    Amos, Christopher I
    Sellers, Thomas A
    Easton, Douglas F
    Hunter, David J
    Haiman, Christopher A
    Henderson, Brian E
    Hung, Rayjean J
    Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 17, p. 5103-5114Article in journal (Refereed)
    Abstract [en]

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

  • 70. Ferrari, Pietro
    et al.
    Freisling, Heinz
    Duell, Eric J
    Kaaks, Rudolf
    Lujan-Barroso, Leila
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Nailler, Laura
    Polidoro, Silvia
    Mattiello, Amalia
    Palli, Domenico
    Tumino, Rosario
    Grioni, Sara
    Knüppel, Sven
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Orfanos, Philippos
    Katsoulis, Michail
    Trichopoulou, Antonia
    Quirós, Jose Ramón
    Ardanaz, Eva
    Huerta, José María
    Etxezarreta, Pilar Amiano
    Sánchez, María José
    Crowe, Francesca
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Ocke, Marga
    Bueno-de-Mesquita, Bas
    Peeters, Petra H M
    Ericson, Ulrika
    Wirfält, Elisabet
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engeset, Dagrun
    Nicolas, Geneviève
    Gallo, Valentina
    Norat, Teresa
    Riboli, Elio
    Slimani, Nadia
    Challenges in estimating the validity of dietary acrylamide measurements2013In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, no 5, p. 1503-1512Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acrylamide is a chemical compound present in tobacco smoke and food, classified as a probable human carcinogen and a known human neurotoxin. Acrylamide is formed in foods, typically carbohydrate-rich and protein-poor plant foods, during high-temperature cooking or other thermal processing. The objectives of this study were to compare dietary estimates of acrylamide from questionnaires (DQ) and 24-h recalls (R) with levels of acrylamide adduct (AA) in haemoglobin.

    METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, acrylamide exposure was assessed in 510 participants from 9 European countries, randomly selected and stratified by age, sex, with equal numbers of never and current smokers. After adjusting for country, alcohol intake, smoking status, number of cigarettes and energy intake, correlation coefficients between various acrylamide measurements were computed, both at the individual and at the aggregate (centre) level.

    RESULTS: Individual level correlation coefficient between DQ and R measurements (r DQ,R) was 0.17, while r DQ,AA and r R,AA were 0.08 and 0.06, respectively. In never smokers, r DQ,R, r DQ,AA and r R,AA were 0.19, 0.09 and 0.02, respectively. The correlation coefficients between means of DQ, R and AA measurements at the centre level were larger (r > 0.4).

    CONCLUSIONS: These findings suggest that estimates of total acrylamide intake based on self-reported diet correlate weakly with biomarker AA Hb levels. Possible explanations are the lack of AA levels to capture dietary acrylamide due to individual differences in the absorption and metabolism of acrylamide, and/or measurement errors in acrylamide from self-reported dietary assessments, thus limiting the possibility to validate acrylamide DQ measurements.

  • 71. Fortner, Renée T
    et al.
    Schock, Helena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Surcel, Helja-Marja
    Early pregnancy sex steroids and maternal breast cancer: a nested case-control study2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 23, p. 6958-6967Article in journal (Refereed)
    Abstract [en]

    Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.

  • 72. Freisling, Heinz
    et al.
    Pisa, Pedro T
    Ferrari, Pietro
    Byrnes, Graham
    Moskal, Aurelie
    Dahm, Christina C
    Vergnaud, Anne-Claire
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cadeau, Claire
    Kühn, Tilman
    Neamat-Allah, Jasmine
    Buijsse, Brian
    Boeing, Heiner
    Halkjær, Jytte
    Tjonneland, Anne
    Hansen, Camilla P
    Quirós, J Ramón
    Travier, Noémie
    Molina-Montes, Esther
    Amiano, Pilar
    Huerta, José M
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas
    Key, Tim J
    Romaguera, Dora
    Lu, Yunxia
    Lassale, Camille M
    Naska, Androniki
    Orfanos, Philippos
    Trichopoulou, Antonia
    Masala, Giovanna
    Pala, Valeria
    Berrino, Franco
    Tumino, Rosario
    Ricceri, Fulvio
    de Magistris, Maria Santucci
    Bueno-de-Mesquita, H Bas
    Ocké, Marga C
    Sonestedt, Emily
    Ericson, Ulrika
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Skeie, Guri
    Weiderpass, Elisabete
    Braaten, Tonje
    Peeters, Petra H M
    Slimani, Nadia
    Main nutrient patterns are associated with prospective weight change in adults from 10 European countries2016In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 55, no 6, p. 2093-2104Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Various food patterns have been associated with weight change in adults, but it is unknown which combinations of nutrients may account for such observations. We investigated associations between main nutrient patterns and prospective weight change in adults.

    METHODS: This study includes 235,880 participants, 25-70 years old, recruited between 1992 and 2000 in 10 European countries. Intakes of 23 nutrients were estimated from country-specific validated dietary questionnaires using the harmonized EPIC Nutrient DataBase. Four nutrient patterns, explaining 67 % of the total variance of nutrient intakes, were previously identified from principal component analysis. Body weight was measured at recruitment and self-reported 5 years later. The relationship between nutrient patterns and annual weight change was examined separately for men and women using linear mixed models with random effect according to center controlling for confounders.

    RESULTS: Mean weight gain was 460 g/year (SD 950) and 420 g/year (SD 940) for men and women, respectively. The annual differences in weight gain per one SD increase in the pattern scores were as follows: principal component (PC) 1, characterized by nutrients from plant food sources, was inversely associated with weight gain in men (-22 g/year; 95 % CI -33 to -10) and women (-18 g/year; 95 % CI -26 to -11). In contrast, PC4, characterized by protein, vitamin B2, phosphorus, and calcium, was associated with a weight gain of +41 g/year (95 % CI +2 to +80) and +88 g/year (95 % CI +36 to +140) in men and women, respectively. Associations with PC2, a pattern driven by many micro-nutrients, and with PC3, a pattern driven by vitamin D, were less consistent and/or non-significant.

    CONCLUSIONS: We identified two main nutrient patterns that are associated with moderate but significant long-term differences in weight gain in adults.

  • 73. Fretts, Amanda M.
    et al.
    Follis, Jack L.
    Nettleton, Jennifer A.
    Lemaitre, Rozenn N.
    Ngwa, Julius S.
    Wojczynski, Mary K.
    Kalafati, Ioanna Panagiota
    Varga, Tibor V.
    Frazier-Wood, Alexis C.
    Houston, Denise K.
    Lahti, Jari
    Ericson, Ulrika
    van den Hooven, Edith H.
    Mikkilae, Vera
    Kiefte-de Jong, Jessica C.
    Mozaffarian, Dariush
    Rice, Kenneth
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    North, Kari E.
    McKeown, Nicola M.
    Feitosa, Mary F.
    Kanoni, Stavroula
    Smith, Caren E.
    Garcia, Melissa E.
    Tiainen, Anna-Maija
    Sonestedt, Emily
    Manichaikul, Ani
    van Rooij, Frank J. A.
    Dimitriou, Maria
    Raitakari, Olli
    Pankow, James S.
    Djousse, Luc
    Province, Michael A.
    Hu, Frank B.
    Lai, Chao-Qiang
    Keller, Margaux F.
    Peraelae, Mia-Maria
    Rotter, Jerome I.
    Hofman, Albert
    Graff, Misa
    Kaehoenen, Mika
    Mukamal, Kenneth
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ordovas, Jose M.
    Liu, Yongmei
    Maennistoe, Satu
    Uitterlinden, Andre G.
    Deloukas, Panos
    Seppaelae, Ilkka
    Psaty, Bruce M.
    Cupples, L. Adrienne
    Borecki, Ingrid B.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA.
    Arnett, Donna K.
    Nalls, Mike A.
    Eriksson, Johan G.
    Orho-Melander, Marju
    Franco, Oscar H.
    Lehtimaeki, Terho
    Dedoussis, George V.
    Meigs, James B.
    Siscovick, David S.
    Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 102, no 5, p. 1266-1278Article in journal (Refereed)
    Abstract [en]

    Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined l) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-1n-pmon (95% CI: 0.035, 0.063-1n-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. Conclusion: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms.

  • 74. Fritz, Josef
    et al.
    Bjorge, Tone
    Nagel, Gabriele
    Concin, Hans
    Manjer, Jonas
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Uppsala universitet.
    Stattin, Pär
    Stocks, Tanja
    Ulmer, Hanno
    Insulin resistance measured by the triglyceride-glucose index and risk of obesity-related cancers: An epidemiological investigation in more than 500,000 individuals.2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15, p. 1552-1552Article in journal (Other academic)
    Abstract [en]

    Background: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. We aimed to determine to what extent insulin resistance measured as the logarithmized triglyceride glucose product (TyG index) mediates the effect of BMI on risk of obesity-related cancers. Methods: A total of 510,471 individuals from six European cohorts with a mean age of 43.1 years were included in the study. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with ten common obesity-related cancer sites, and quantified the proportion of the effect of BMI mediated through TyG index. Results: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney (hazard ratio (HR) per one standard deviation increase 1.13, 95% confidence interval: 1.07-1.20), liver (1.13, 1.04-1.23), pancreas (1.12, 1.06-1.19), colon (1.07, 1.03-1.10), and rectum (1.09, 1.04-1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%), and colon (20%); smaller proportions for kidney (15%) and liver (11%); none for endometrium, ovary and breast (postmenopausal). Conclusions: In this pooled cohort study including more than 500,000 individuals, insulin resistance measured as the logarithmized triglyceride glucose product significantly mediated the effect of overweight and obesity on risk of cancers of the kidney, liver, pancreas, colon, and rectum. In contrast, insulin resistance did not mediate the risk for cancers of the endometrium, ovary and breast. Our results confirm a promoting role of insulin resistance in the pathogenesis of gastrointestinal cancers. Although often claimed, insulin resistance does not appear to connect excess body weight with cancers of the female reproductive organs.

  • 75. Fritz, Josef
    et al.
    Bjørge, Tone
    Nagel, Gabriele
    Manjer, Jonas
    Engeland, Anders
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Concin, Hans
    Teleka, Stanley
    Tretli, Steinar
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lang, Alois
    Stattin, Pär
    Stocks, Tanja
    Ulmer, Hanno
    The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers2019In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, p. 1-12, article id dyz053Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified.

    METHODS: Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale.

    RESULTS: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively.

    CONCLUSIONS: The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.

  • 76. Gallo, Valentina
    et al.
    Wark, Petra A.
    Jenab, Mazda
    Pearce, Neil
    Brayne, Carol
    Vermeulen, Roel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kyrozis, Andreas
    Vanacore, Nicola
    Vahdaninia, Mariam
    Grote, Verena
    Kaaks, Rudolf
    Mattiello, Amalia
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Travis, Ruth C.
    Petersson, Jesper
    Hansson, Oskar
    Arriola, Larraitz
    Jimenez-Martin, Juan-Manuel
    Tjonneland, Anne
    Halkjaer, Jytte
    Agnoli, Claudia
    Sacerdote, Carlotta
    Bonet, Catalina
    Trichopoulou, Antonia
    Gavrila, Diana
    Overvad, Kim
    Weiderpass, Elisabete
    Palli, Domenico
    Ramon Quiros, J.
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Barricante-Gurrea, Aurelio
    Fedirko, Veronika
    Ferrari, Pietro
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Boeing, Heiner
    Vigl, Matthaeus
    Middleton, Lefkos
    Riboli, Elio
    Vineis, Paolo
    Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis The EPIC cohort2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 9, p. 829-838Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. Methods: The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality. Results: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86-0.99 per kg/m(2)); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p = 0.056). Conclusion: Increased prediagnostic body fat is associated with a decreased risk of ALS mortality. Neurology (R) 2013; 80: 829-838

  • 77. Gasull, Magda
    et al.
    Pumarega, José
    Kiviranta, Hannu
    Rantakokko, Panu
    Raaschou-Nielsen, Ole
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sandanger, Torkjel Manning
    Goñi, Fernando
    Cirera, Lluís
    Donat-Vargas, Carolina
    Alguacil, Juan
    Iglesias, Mar
    Tjønneland, Anne
    Overvad, Kim
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Johnson, Theron
    Kühn, Tilman
    Trichopoulou, Antonia
    Karakatsani, Anna
    Peppa, Eleni
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Verschuren, Monique
    Vermeulen, Roel
    Rylander, Charlotta
    Haugdahl Nøst, Therese
    Rodríguez-Barranco, Miguel
    Molinuevo, Amaia
    Chirlaque, María-Dolores
    Ardanaz, Eva
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Key, Tim
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm, Sweden.
    Jenab, Mazda
    Michaud, Dominique
    Matullo, Giuseppe
    Canzian, Federico
    Kaaks, Rudolf
    Nieters, Alexandra
    Nöthlings, Ute
    Jeurnink, Suzanne
    Chajes, Veronique
    Matejcic, Marco
    Gunter, Marc
    Aune, Dagfinn
    Riboli, Elio
    Agudo, Antoni
    Gonzalez, Carlos Alberto
    Weiderpass, Elisabete
    Bueno-de-Mesquita, Bas
    Duell, Eric J.
    Vineis, Paolo
    Porta, Miquel
    Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort2019In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 169, p. 417-433Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.

    OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.

    METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.

    RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.

    CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.

  • 78. Gaudet, Mia M
    et al.
    Deubler, Emily L
    Kelly, Rachel S
    Diver, W Ryan
    Teras, Lauren R
    Hodge, James M
    Levine, Keith E
    Haines, Laura G
    Lundh, Thomas
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Palli, Domenico
    Vineis, Paolo
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Gapstur, Susan M
    Kyrtopoulos, Soterios A
    Blood Levels of Cadmium and Lead in Relation to Breast Cancer Risk in Three Prospective Cohorts.2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 5, p. 1010-1016Article in journal (Refereed)
    Abstract [en]

    Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy), and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR=1.01, 95% CI 0.76 - 1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR=0.80, 95% CI 0.61 - 1.03) and NSHDS cohorts (continuous RR=0.73, 95% CI 0.54 - 0.97). The inverse association was also evident in the meta-analysis (continuous RR=0.84, 95% CI 0.69 - 1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis. 

  • 79. Ge, Wenzhen
    et al.
    Clendenen, Tess V.
    Afanasyeva, Yelena
    Koenig, Karen L.
    Agnoli, Claudia
    Brinton, Louise A.
    Dorgan, Joanne F.
    Eliassen, A. Heather
    Falk, Roni T.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E.
    Hoffman-Bolton, Judith
    Key, Timothy J.
    Krogh, Vittorio
    Nichols, Hazel B.
    Sandler, Dale P.
    Schoemaker, Minouk J.
    Sluss, Patrick M.
    Sund, Malin
    Department of Surgery, Umeå University Hospital, Umeå, Sweden.
    Swerdlow, Anthony J.
    Visvanathan, Kala
    Liu, Mengling
    Zeleniuch-Jacquotte, Anne
    Circulating anti-Müllerian hormone and breast cancer risk: a study in ten prospective cohorts2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 11, p. 2215-2226Article in journal (Refereed)
    Abstract [en]

    A strong positive association has been observed between circulating anti‐Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case–control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme‐linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (ptrend across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31–1.94). Though the test for interaction was not statistically significant (pinteraction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: ORQ4–Q1 = 1.96, 95% CI = 1.46–2.64, ptrend <0.0001; ER+/PR−: ORQ4–Q1 = 0.82, 95% CI = 0.40–1.68, ptrend = 0.51; ER−/PR+: ORQ4–Q1 = 3.23, 95% CI = 0.48–21.9, ptrend = 0.26; ER−/PR−: ORQ4–Q1 = 1.15, 95% CI = 0.63–2.09, ptrend = 0.60. The association was observed for both pre‐ (ORQ4–Q1= 1.35, 95% CI = 1.05–1.73) and post‐menopausal (ORQ4–Q1 = 1.61, 95% CI = 1.03–2.53) breast cancer (pinteraction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.

    What's new? To make informed decisions about screening and prevention, women need tools to accurately assess their breast cancer risk. Young women have few predictive biomarkers to look to; estrogen and progesterone are only weakly predictive before menopause. Anti-Müllerian hormone (AMH), which strongly correlates with age at menopause, may also correlate with breast cancer risk, according to some previous data. Here, the authors test this correlation by conducting nested case-control studies within ten different cohorts. They found that breast cancer risk increased along with increasing AMH concentration, confirming this hormone as a possible biomarker for breast cancer.

  • 80. Georgiadis, Panagiotis
    et al.
    Gavriil, Marios
    Rantakokko, Panu
    Ladoukakis, Efthymios
    Botsivali, Maria
    Kelly, Rachel S
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Kiviranta, Hannu
    Vermeulen, Roel C H
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hebbels, Dennie G A J
    Kleinjans, Jos C S
    de Kok, Theo M C M
    Palli, Domenico
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia2019In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 126, p. 24-36Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma.

    METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene.

    RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis.

    CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals.

  • 81. Georgiadis, Panagiotis
    et al.
    Hebels, Dennie G
    Valavanis, Ioannis
    Liampa, Irene
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palli, Domenico
    Chadeau-Hyam, Marc
    Chatziioannou, Aristotelis
    Jennen, Danyel G J
    Krauskopf, Julian
    Jetten, Marlon J
    Kleinjans, Jos C S
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Omics for prediction of environmental health effects: Blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking.2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20544Article in journal (Refereed)
    Abstract [en]

    The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.

  • 82. Georgiadis, Panagiotis
    et al.
    Liampa, Irene
    Hebels, Dennie G
    Krauskopf, Julian
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    de Kok, Theo M C M
    Kleinjans, Jos C S
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palli, Domenico
    Vermeulen, R C H
    Vlaanderen, J
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 728Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

    RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

    CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

  • 83. Graff, Mariaelisa
    et al.
    Scott, Robert A.
    Justice, Anne E.
    Young, Kristin L.
    Feitosa, Mary F.
    Barata, Llilda
    Winkler, Thomas W.
    Chu, Audrey Y.
    Mahajan, Anubha
    Hadley, David
    Xue, Luting
    Workalemahu, Tsegaselassie
    Heard-Costa, Nancy L.
    den Hoed, Marcel
    Ahluwalia, Tarunveer S.
    Qi, Qibin
    Ngwa, Julius S.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden.
    Quaye, Lydia
    Eicher, John D.
    Hayes, James E.
    Cornelis, Marilyn
    Kutalik, Zoltan
    Lim, Elise
    Luan, Jian'an
    Huffman, Jennifer E.
    Zhang, Weihua
    Zhao, Wei
    Griffin, Paula J.
    Haller, Toomas
    Ahmad, Shafqat
    Marques-Vidal, Pedro M.
    Bien, Stephanie
    Yengo, Loic
    Teumer, Alexander
    Smith, Albert Vernon
    Kumari, Meena
    Harder, Marie Neergaard
    Justesen, Johanne Marie
    Kleber, Marcus E.
    Hollensted, Mette
    Lohman, Kurt
    Rivera, Natalia V.
    Whitfield, John B.
    Zhao, Jing Hua
    Stringham, Heather M.
    Lyytikainen, Leo-Pekka
    Huppertz, Charlotte
    Willemsen, Gonneke
    Peyrot, Wouter J.
    Wu, Ying
    Kristiansson, Kati
    Demirkan, Ayse
    Fornage, Myriam
    Hassinen, Maija
    Bielak, Lawrence F.
    Cadby, Gemma
    Tanaka, Toshiko
    Magl, Reedlk
    Van der Most, Peter J.
    Jackson, Anne U.
    Bragg-Gresham, Jennifer L.
    Vitart, Veronique
    Marten, Jonathan
    Navarro, Pau
    Bellis, Claire
    Pasko, Dorota
    Johansson, Asa
    Snitker, Soren
    Cheng, Yu-Ching
    Eriksson, Joel
    Lim, Unhee
    Aadahl, Mette
    Adair, Linda S.
    Amin, Najaf
    Balkau, Beverley
    Auvinen, Juha
    Beilby, John
    Bergman, Richard N.
    Bergmann, Sven
    Bertoni, Alain G.
    Blangero, John
    Bonnefond, Amelle
    Bonnycastle, Lori L.
    Borja, Judith B.
    Brage, Soren
    Busonero, Fabio
    Buyske, Steve
    Campbell, Harry
    Chines, Peter S.
    Collins, Francis S.
    Corre, Tanguy
    Smith, George Davey
    Delgado, Graciela E.
    Dueker, Nicole
    Doerr, Marcus
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tonu
    Faul, Jessica D.
    Fu, Mao
    Faerch, Kristine
    Gieger, Christian
    Glaeser, Sven
    Gong, Jian
    Gordon-Larsen, Penny
    Grallert, Harald
    Grammer, Tanja B.
    Grarup, Niels
    van Grootheest, Gerard
    Harald, Kennet
    Hastie, Nicholas D.
    Havulinna, Aki S.
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J.
    Holmens, Oddgeir L.
    Holzapfel, Christina
    Hottenga, Jouke Jan
    Huang, Jie
    Huang, Tao
    Hui, Jennie
    Huth, Cornelia
    Hutri-Kahonen, Nina
    James, Alan L.
    Jansson, John-Olov
    Jhun, Min A.
    Juonala, Markus
    Kinnunen, Leena
    Koistinen, Heikki A.
    Kolcic, Ivana
    Komulainen, Pirjo
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Kahonen, Mika
    Lakka, Timo A.
    Launer, Lenore J.
    Lehne, Benjamin
    Lindgren, Cecilia M.
    Lorentzon, Mattias
    Luben, Robert
    Marre, Michel
    Milaneschi, Yuri
    Monda, Keri L.
    Montgomery, Grant W.
    De Moor, Marleen H. M.
    Mulas, Antonella
    Mueller-Nurasyid, Martina
    Musk, A. W.
    Mannikko, Reija
    Mannisto, Satu
    Narisu, Narisu
    Nauck, Matthias
    Nettleton, Jennifer A.
    Nolte, Ilja M.
    Oldehinkel, Albertine J.
    Olden, Matthias
    Ong, Ken K.
    Padmanabhan, Sandosh
    Paternoster, Lavinia
    Perez, Jeremiah
    Perola, Markus
    Peters, Annette
    Peters, Ulrike
    Peyser, Patricia A.
    Prokopenko, Inga
    Puolijoki, Hannu
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J.
    Rawal, Rajesh
    Ridker, Paul M.
    Rose, Lynda M.
    Rudan, Igor
    Sarti, Cinzia
    Sarzynski, Mark A.
    Savonen, Kai
    Scott, William R.
    Sanna, Serena
    Shuldiner, Alan R.
    Sidney, Steve
    Silbernagel, Guenther
    Smith, Blair H.
    Smith, Jennifer A.
    Snieder, Harold
    Stancakova, Alena
    Sternfeld, Barbara
    Swift, Amy J.
    Tammelin, Tuija
    Tan, Sian-Tsung
    Thorand, Barbara
    Thuillier, Dorothee
    Vandenput, Liesbeth
    Vestergaard, Henrik
    van Vliet-Ostaptchouk, Jana V.
    Vohl, Marie-Claude
    Voelker, Uwe
    Waeber, Gerard
    Walker, Mark
    Wild, Sarah
    Wong, Andrew
    Wright, Alan F.
    Zillikens, M. Carola
    Zubair, Niha
    Haiman, Christopher A.
    Lemarchand, Loic
    Gyllensten, Ulf
    Ohlsson, Claes
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Perusse, Louis
    Wilson, James F.
    Hayward, Caroline
    Polasek, Ozren
    Cucca, Francesco
    Hveem, Kristian
    Hartman, Catharina A.
    Toenjes, Anke
    Bandinelli, Stefania
    Palmer, Lyle J.
    Kardia, Sharon L. R.
    Rauramaa, Rainer
    Sorensen, Thorkild I. A.
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Penninx, Brenda W. J. H.
    de Geus, Eco J. C.
    Boomsma, Dorret I.
    Lehtimaki, Terho
    Mangino, Massimo
    Laakso, Markku
    Bouchard, Claude
    Martin, Nicholas G.
    Kuh, Diana
    Liu, Yongmei
    Linneberg, Allan
    Maerz, Winfried
    Strauch, Konstantin
    Kivimaki, Mika
    Harris, Tamara B.
    Gudnason, Vilmundur
    Voelzke, Henry
    Qi, Lu
    Jarvelin, Marjo-Riitta
    Chambers, John C.
    Kooner, Jaspal S.
    Froguel, Philippe
    Kooperberg, Charles
    Vollenweider, Peter
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hansen, Torben
    Pedersen, Oluf
    Metspalu, Andres
    Wareham, Nicholas J.
    Langenberg, Claudia
    Weir, David R.
    Porteous, David J.
    Boerwinkle, Eric
    Chasman, Daniel I.
    Abecasis, Goncalo R.
    Barroso, Ines
    McCarthy, Mark I.
    Frayling, Timothy M.
    O'Connell, Jeffrey R.
    van Duijn, Cornelia M.
    Boehnke, Michael
    Heid, Iris M.
    Mohlke, Karen L.
    Strachan, David P.
    Fox, Caroline S.
    Liu, Ching-Ti
    Hirschhorn, Joel N.
    Klein, Robert J.
    Johnson, Andrew D.
    Borecki, Ingrid B.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA ; Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden.
    North, Kari E.
    Cupples, L. Adrienne
    Loos, Ruth J. F.
    Kilpelainen, Tuomas O.
    Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006528Article in journal (Refereed)
    Abstract [en]

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

  • 84. Grøntved, Anders
    et al.
    Koivula, Robert W
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Østergaard, Lars
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Skåne University Hospital Malmö, Malmö, Sweden.
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Skåne University Hospital Malmö, Malmö, Sweden.
    Bicycling to Work and Primordial Prevention of Cardiovascular Risk: A Cohort Study Among Swedish Men and Women2016In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 11, article id e004413Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bicycling to work may be a viable approach for achieving physical activity that provides cardiovascular health benefits. In this study we investigated the relationship of bicycling to work with incidence of obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance across a decade of follow-up in middle-aged men and women.

    METHODS AND RESULTS: We followed 23 732 Swedish men and women with a mean age of 43.5 years at baseline who attended a health examination twice during a 10-year period (1990-2011). In multivariable adjusted models we calculated the odds of incident obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance, comparing individuals who commuted to work by bicycle with those who used passive modes of transportation. We also examined the relationship of change in commuting mode with incidence of these clinical risk factors. Cycling to work at baseline was associated with lower odds of incident obesity (odds ratio [OR]=0.85, 95% CI 0.73-0.99), hypertension (OR=0.87, 95% CI 0.79-0.95), hypertriglyceridemia (OR=0.85, 95% CI 0.76-0.94), and impaired glucose tolerance (OR=0.88, 95% CI 0.80-0.96) compared with passive travel after adjusting for putative confounding factors. Participants who maintained or began bicycling to work during follow-up had lower odds of obesity (OR=0.61, 95% CI 0.50-0.73), hypertension (OR=0.89, 95% CI 0.80-0.98), hypertriglyceridemia (OR=0.80, 95% CI 0.70-0.90), and impaired glucose tolerance (OR=0.82, 95% CI 0.74-0.91) compared with participants not cycling to work at both times points or who switched from cycling to other modes of transport during follow-up.

    CONCLUSIONS: These data suggest that commuting by bicycle to work is an important strategy for primordial prevention of clinical cardiovascular risk factors among middle-aged men and women.

  • 85. Gusev, Alexander
    et al.
    Shi, Huwenbo
    Kichaev, Gleb
    Pomerantz, Mark
    Li, Fugen
    Long, Henry W
    Ingles, Sue A
    Kittles, Rick A
    Strom, Sara S
    Rybicki, Benjamin A
    Nemesure, Barbara
    Isaacs, William B
    Zheng, Wei
    Pettaway, Curtis A
    Yeboah, Edward D
    Tettey, Yao
    Biritwum, Richard B
    Adjei, Andrew A
    Tay, Evelyn
    Truelove, Ann
    Niwa, Shelley
    Chokkalingam, Anand P
    John, Esther M
    Murphy, Adam B
    Signorello, Lisa B
    Carpten, John
    Leske, M Cristina
    Wu, Suh-Yuh
    Hennis, Anslem J M
    Neslund-Dudas, Christine
    Hsing, Ann W
    Chu, Lisa
    Goodman, Phyllis J
    Klein, Eric A
    Witte, John S
    Casey, Graham
    Kaggwa, Sam
    Cook, Michael B
    Stram, Daniel O
    Blot, William J
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, ZSofia
    Al Olama, Ali Amin
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Henderson, Brian E
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Kluzniak, Wojciech
    Cannon-Albright, Lisa
    Teerlink, Craig
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Teixeira, Manuel R
    Pandha, Hardev
    Michael, Agnieszka
    Paulo, Paula
    Maia, Sofia
    Kierzek, Andrzej
    Conti, David V
    Albanes, Demetrius
    Berg, Christine
    Berndt, Sonja I
    Campa, Daniele
    Crawford, E David
    Diver, W Ryan
    Gapstur, Susan M
    Gaziano, J Michael
    Giovannucci, Edward
    Hoover, Robert
    Hunter, David J
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kraft, Peter
    Le Marchand, Loic
    Lindström, Sara
    Navarro, Carmen
    Overvad, Kim
    Riboli, Elio
    Siddiq, Afshan
    Stevens, Victoria L
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Yeager, Meredith
    Trynka, Gosia
    Raychaudhuri, Soumya
    Schumacher, Frederick R
    Price, Alkes L
    Freedman, Matthew L
    Haiman, Christopher A
    Pasaniuc, Bogdan
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10979Article in journal (Refereed)
    Abstract [en]

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  • 86.
    Gylling, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schneede, Jørn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Häggstrom, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ulvik, Arve
    Ueland, Per M.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vitamin B-6 and colorectal cancer risk: a prospective population-based study using 3 distinct plasma markers of vitamin B-6 status2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 105, no 4, p. 897-904Article in journal (Refereed)
    Abstract [en]

    Background: Higher plasma concentrations of the vitamin B-6 marker pyridoxal 5#-phosphate (PLP) have been associated with reduced colorectal cancer (CRC) risk. Inflammatory processes, including vitamin B-6 catabolism, could explain such findings. Objective: We investigated 3 biomarkers of vitamin B-6 status in relation to CRC risk. Design: This was a prospective case-control study of 613 CRC cases and 1190 matched controls nested within the Northern Sweden Health and Disease Study (n = 114,679). Participants were followed from 1985 to 2009, and the median follow-up from baseline to CRC diagnosis was 8.2 y. PLP, pyridoxal, pyridoxic acid (PA), 3-hydroxykynurenine, and xanthurenic acids (XAs) were measured in plasma with the use of liquid chromatography-tandem mass spectrometry. We calculated relative and absolute risks of CRC for PLP and the ratios 3-hydroxykynurenine: XA (HK: XA), an inverse marker of functional vitamin B-6 status, and PA:(PLP + pyridoxal) (PAr), a marker of inflammation and oxidative stress and an inverse marker of vitamin B-6 status. Results: Plasma PLP concentrations were associated with a reduced CRC risk for the third compared with the first quartile and for PLP sufficiency compared with deficiency [OR: 0.60 (95% CI: 0.44, 0.81) and OR: 0.55 (95% CI: 0.37, 0.81), respectively]. HK: XA and PAr were both associated with increased CRC risk [OR: 1.48 (95% CI: 1.08, 2.02) and OR: 1.50 (95% CI: 1.10, 2.04), respectively] for the fourth compared with the first quartile. For HK: XA and PAr, the findings were mainly observed in study participants with,10.5 y of follow-up between sampling and diagnosis. Conclusions: Vitamin B-6 deficiency as measured by plasma PLP is associated with a clear increase in CRC risk. Furthermore, our analyses of novel markers of functional vitamin B-6 status and vitamin B-6-associated oxidative stress and inflammation suggest a role in tumor progression rather than initiation.

  • 87.
    Gylling, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ueland, Per Magne
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 10, p. 2136-2144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer.

    METHODS: This was a prospective case-control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years.

    RESULTS: Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08-2.42] and 1.42 (95% CI, 0.94-2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk.

    CONCLUSIONS: In this population-based, nested case-control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions.

    IMPACT: These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour.

  • 88. Hebels, Dennie G. A. J.
    et al.
    Georgiadis, Panagiotis
    Keun, Hector C.
    Athersuch, Toby J.
    Vineis, Paolo
    Vermeulen, Roel
    Portengen, Lützen
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palli, Domenico
    Bendinelli, Benedetta
    Krogh, Vittorio
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Kleinjans, Jos C. S.
    de Kok, Theo M. C. M.
    Smith, Martyn T.
    Kyrtopoulos, Soterios A.
    Performance in omics analyses of blood samples in long-term storage: opportunities for the exploitation of existing biobanks in environmental health research2013In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, no 4, p. 480-487Article in journal (Refereed)
    Abstract [en]

    Background: The suitability for omic analysis of biosamples collected in previous decades and currently stored in biobanks is unknown.

    Objectives: We evaluated the influence of handling and storage conditions of blood-derived biosamples on transcriptomic, epigenomic (CpG methylation), plasma metabolomic [UPLC-ToFMS (ultra performance liquid chromatography-time-of-flight mass spectrometry)], and wide-target proteomic profiles.

    Methods: We collected fresh blood samples without RNA preservative in heparin, EDTA, or citrate and held them at room temperature for ≤ 24 hr before fractionating them into buffy coat, erythrocytes, and plasma and freezing the fractions at -80oC or in liquid nitrogen. We developed methodology for isolating RNA from the buffy coats and conducted omic analyses. Finally, we analyzed analogous samples from the EPIC-Italy and Northern Sweden Health and Disease Study biobanks.

    Results: Microarray-quality RNA could be isolated from buffy coats (including most biobank samples) that had been frozen within 8 hr of blood collection by thawing the samples in RNA preservative. Different anticoagulants influenced the metabolomic, proteomic, and to a lesser extent transcriptomic profiles. Transcriptomic profiles were most affected by the delay (as little as 2 hr) before blood fractionation, whereas storage temperature had minimal impact. Effects on metabolomic and proteomic profiles were noted in samples processed ≥ 8 hr after collection, but no effects were due to storage temperature. None of the variables examined significantly influenced the epigenomic profiles. No systematic influence of time-in-storage was observed in samples stored over a period of 13-17 years.

    Conclusions: Most samples currently stored in biobanks are amenable to meaningful omics analysis, provided that they satisfy collection and storage criteria defined in this study.

  • 89. Hemminki, Kari
    et al.
    Chen, Bowang
    Kumar, Abhishek
    Melander, Olle
    Manjer, Jonas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ohlsson, Claes
    Folprecht, Gunnar
    Löffler, Harald
    Krämer, Alwin
    Försti, Asta
    Germline genetics of cancer of unknown primary (CUP) and its specific subtypes2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 16, p. 22140-22149Article in journal (Refereed)
    Abstract [en]

    Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10-7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5'UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.

  • 90. Hemminki, Kari
    et al.
    Chen, Bowang
    Melander, Olle
    Manjer, Jonas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hemminki, Akseli
    Smoking and body mass index as risk factors for subtypes of cancer of unknown primary2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 1, p. 246-247Article in journal (Refereed)
  • 91.
    Holmgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ljungberg, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    TroponinT but not C-reactive protein is associated with future surgery for aortic stenosis - a population based nested case-refeent study.Manuscript (preprint) (Other academic)
  • 92.
    Holmgren, Klas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Department of Surgery, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Preoperative biomarkers related to inflammation identify high-risk anastomoses in surgery for rectal cancer: an explorative study on patients with colorectal cancerManuscript (preprint) (Other academic)
  • 93. Hosnijeh, Fatemeh Saberi
    et al.
    Portengen, Lutzen
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mattiello, Amalia
    Masala, Giovanna
    Sacerdote, Carlotta
    Naccarati, Alessio
    Krogh, Vittorio
    Tumino, Rosario
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Vermeulen, Roel
    Soluble B-cell activation marker of sCD27 and sCD30 and future risk of B-cell lymphomas: a nested case-control study and meta-analyses2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 138, no 10, p. 2357-2367Article in journal (Refereed)
    Abstract [en]

    Pre-diagnostic serum/plasma concentrations of B-cell activation markers have been associated with future risk of B-cell lymphomas (BCL) in HIV-infected patients and in the general population. Current evidence for the general population is however limited and relies on relatively small numbers of observations, especially for specific histologies. We carried out a nested case-control study, including 218 BCL and 218 matched controls, within two prospective cohorts, to investigate the association between plasma levels of soluble (s)CD27 and sCD30 and future risk of BCL, and main histologic subtypes separately. To expand the evidence further, we performed meta-analyses of the published data on these associations from prospective studies among the general population. Our study revealed a significant relationship between sCD30 concentration and BCL risk (OR=0.86, 1.53, 1.76, for the 2(nd) -4(th) quartiles respectively, P-trend=0.01). Similar increased risks were observed for diffuse large B-cell lymphoma and follicular lymphoma. Analyses of sCD27 blood concentrations did not show significant associations with BCL, (OR=0.90, 1.26, 1.65 for the 2(nd) -4(th) quartiles, respectively, P-trend=0.17), but significant associations were observed for chronic lymphocytic leukaemia and for the group of 'other BCL' subtypes. Our findings involving sCD30 were confirmed within our meta-analyses of five prospective cohorts, while results were more heterogeneous for sCD27 with the exception of CLL which was found consistently in all studies. Data to date suggest that chronic B-cell stimulation might be an important mechanism involved in B-cell lymphomagenesis both in HIV-infected and in the general population.

  • 94. Hruby, Adela
    et al.
    Ngwa, Julius S.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wojczynski, Mary K.
    Ganna, Andrea
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Houston, Denise K.
    Jacques, Paul F.
    Kanoni, Stavroula
    Lehtimaki, Terho
    Lemaitre, Rozenn N.
    Manichaikul, Ani
    North, Kari E.
    Ntalla, Ioanna
    Sonestedt, Emily
    Tanaka, Toshiko
    van Rooij, Frank J. A.
    Bandinelli, Stefania
    Djousse, Luc
    Grigoriou, Efi.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Lohman, Kurt K.
    Pankow, James S.
    Raitakari, Olli T.
    Riserus, Ulf
    Yannakoulia, Mary
    Zillikens, M. Carola
    Hassanali, Neelam
    Liu, Yongmei
    Mozaffarian, Dariush
    Papoutsakis, Constantina
    Syvanen, Ann-Christine
    Uitterlinden, Andre G.
    Viikari, Jorma
    Groves, Christopher J.
    Hofman, Albert
    Lind, Lars
    McCarthy, Mark I.
    Mikkila, Vera
    Mukamal, Kenneth
    Franco, Oscar H.
    Borecki, Ingrid B.
    Cupples, L. Adrienne
    Dedoussis, George V.
    Ferrucci, Luigi
    Hu, Frank B.
    Ingelsson, Erik
    Kahonen, Mika
    Kao, W. H. Linda
    Kritchevsky, Stephen B.
    Orho-Melander, Marju
    Prokopenko, Inga
    Rotter, Jerome I.
    Siscovick, David S.
    Witteman, Jacqueline C. M.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Meigs, James B.
    McKeown, Nicola M.
    Nettleton, Jennifer A.
    Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies2013In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 143, no 3, p. 345-353Article in journal (Refereed)
    Abstract [en]

    Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. J. Nutr. 143: 345-353, 2013.

  • 95. Huang, Tao
    et al.
    Ding, Ming
    Bergholdt, Helle K. M.
    Wang, Tiange
    Heianza, Yoriko
    Sun, Dian-jianyi
    Frazier-Wood, Alexis C.
    Aslibekyan, Stella
    North, Kari E.
    Voortman, Trudy
    Graff, Mariaelisa
    Smith, Caren E.
    Lai, Chao-Qiang
    Varbo, Anette
    Lemaitre, Rozenn N.
    de Jonge, M. Ester A. L.
    Fumeron, Fredric
    Corella, Dolores
    Wang, Carol A.
    Tjonneland, Anne
    Overvad, Kim
    Sorensen, Thorkild I. A.
    Feitosa, Mary F.
    Wojczynski, Mary K.
    Kahonen, Mika
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Psaty, Bruce M.
    Siscovick, David S.
    Barroso, Ines
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hernandez, Dena
    Ferrucci, Luigi
    Bandinelli, Stefania
    Linneberg, Allan
    Zillikens, M. Carola
    Sandholt, Camilla Helene
    Pedersen, Oluf
    Hansen, Torben
    Schulz, Christina-Alexandra
    Sonestedt, Emily
    Orho-Melander, Marju
    Chen, Tzu-An
    Rotter, Jerome I.
    Allison, Mathew A.
    Rich, Stephen S.
    Sorli, Jose V.
    Coltell, Oscar
    Pennell, Craig E.
    Eastwood, Peter
    Hofman, Albert
    Uitterlinden, Andre G.
    van Rooij, Frank J. A.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ridker, Paul M.
    Viikari, Jorma
    Raitakari, Olli
    Lehtimaki, Terho
    Mikkila, Vera
    Willett, Walter C.
    Wang, Yujie
    Tucker, Katherine L.
    Ordovas, Jose M.
    Kilpelainen, Tuomas O.
    Province, Michael A.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, MA; Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Arnett, Donna K.
    Tanaka, Toshiko
    Toft, Ulla
    Ericson, Ulrika
    Franco, Oscar H.
    Mozaffarian, Dariush
    Hu, Frank B.
    Chasman, Daniel I.
    Nordestgaard, Borge G.
    Ellervik, Christina
    Qi, Lu
    Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 183-191Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.

    METHODS: We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.

    RESULTS: Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4).

    CONCLUSIONS: The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

  • 96.
    Häggstrom, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmert, David
    Lund Univ, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Ulmer, Hanno
    nnsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Innsbruck, Austria.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Manjer, Jonas
    Lund Univ, Dept Plast Surg, Skåne Univ Hosp, Malmö, Sweden.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Nagel, Gabriele
    Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany.
    Almqvist, Martin
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Austria.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prospective study on metabolic factors and risk of prostate cancer2012In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 118, no 24, p. 6199-6206Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There are inconsistent data regarding the association between metabolic factors, separately and combined, and the risk of prostate cancer and death from prostate cancer.

    METHODS: In the Metabolic Syndrome and Cancer Project (Me-Can), data on body mass index (BMI); blood pressure; and blood levels of glucose, cholesterol, and triglycerides were collected for 289,866 men. Cox proportional hazard models were used to calculate relative risks (RRs) by exposures in quintiles as well as for z scores (with a mean of 0 and a standard deviation of 1) together with a composite sum of scores to assess the combined effect of metabolic factors. RRs were corrected for random errors in measurement.

    RESULTS: During a mean follow-up of 12 years, 6673 men were diagnosed with prostate cancer and 961 died of the disease. Men with high levels of glucose and triglycerides were found to have a decreased risk of prostate cancer: top versus bottom quintile of glucose: RR, 0.82 (95% confidence interval [95% CI], 0.62-1.08; P value for trend = .03) and top versus bottom quintile of triglycerides: RR, 0.88 (95% CI, 0.74-1.04; P value for trend = .001). High BMI, elevated blood pressure, and a high composite z score were found to be associated with an increased risk of death from prostate cancer: top versus bottom quintile of BMI: RR, 1.36 (95% CI, 1.08-1.71); systolic blood pressure: RR, 1.62 (95% CI, 1.07-2.45); and per 1-unit increase of the composite z score: RR, 1.13 (95% CI, 1.03-1.25).

    CONCLUSIONS: The authors found no evidence of an association between high levels of metabolic factors and the risk of prostate cancer, but high BMI, elevated blood pressure, and a composite score of all metabolic factors were associated with an increased risk of death from prostate cancer. 

  • 97.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Garmo, Hans
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Van Hemelrijck, Mieke
    Söderkvist, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Aljabery, Firas
    Ströck, Viveka
    Hosseini, Abolfazl
    Gårdmark, Truls
    Malmström, Per-Uno
    Jahnson, Staffan
    Liedberg, Fredrik
    Holmberg, Lars
    Survival after radiotherapy versus radical cystectomy for primary muscle-invasive bladder cancer: A Swedish nationwide population-based cohort study2019In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 5, p. 2196-2204Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies of survival comparing radical cystectomy (RC) and radiotherapy for muscle-invasive bladder cancer have provided inconsistent results and have methodological limitations. The aim of the study was to investigate risk of death after radiotherapy as compared to RC.

    METHODS: We selected patients with muscle-invasive urothelial carcinoma without distant metastases, treated with radiotherapy or RC from 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe) and estimated absolute and relative risk of bladder cancer death and all-cause death. In a group of patients, theoretically eligible for a trial comparing radiotherapy and RC, we calculated risk difference in an instrumental variable analysis. We have not investigated chemoradiotherapy as this treatment was not used in the study time period.

    RESULTS: The study included 3 309 patients, of those 17% were treated with radiotherapy and 83% with RC. Patients treated with radiotherapy were older, had more advanced comorbidity, and had a higher risk of death as compared to patients treated with RC (relative risks of 1.5-1.6). In the "trial population," all-cause death risk difference was 6 per 100 patients lower after radiotherapy at 5 years of follow-up, 95% confidence interval -41 to 29.

    CONCLUSION(S): Patient selection between the treatments make it difficult to evaluate results from conventionally adjusted and propensity-score matched survival analysis. When taking into account unmeasured confounding by instrumental variable analysis, no differences in survival was found between the treatments for a selected group of patients. Further clinical studies are needed to characterize this group of patients, which can serve as a basis for future comparison studies for treatment recommendations.

  • 98.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bjørge, Tone
    Nagel, Gabriele
    Manjer, Jonas
    Ulmer, Hanno
    Drake, Isabel
    Ghaderi, Sara
    Lang, Alois
    Engeland, Anders
    Stattin, Pär
    Stocks, Tanja
    Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals2020In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 1, p. 58-67Article in journal (Refereed)
    Abstract [en]

    Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age‐course. We created two random 50–50% cohorts from six European cohorts comprising 813,927 individuals. In the “discovery cohort”, we used Cox regression with attained age as time‐scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p‐value below 0.05 were additionally tested in the “replication cohort” where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age‐plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age‐interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age‐interactions in breast cancer may suggest an influence by other age‐related factors than menopause; however, further investigation of age‐related effect modifiers in both breast and liver cancer is needed.

  • 99.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Liedberg, Fredrik
    Hagberg, Oskar
    Aljabery, Firas
    Ströck, Viveka
    Hosseini, Abolfazl
    Gårdmark, Truls
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Garmo, Hans
    Jahnson, Staffan
    Holmberg, Lars
    Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe).

    PARTICIPANTS: The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death.

    FINDINGS TO DATE: Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival.

    FUTURE PLANS: The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author.

  • 100.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rapp, Kilian
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Ulmer, Hanno
    Med Univ Innsbruck, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Almqvist, Martin
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Australia.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Nagel, Gabriele
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metabolic factors associated with risk of renal cell carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e57475-Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that obesity and hypertension are associated with increased risk of renal cell carcinoma (RCC), but less is known about the association to other metabolic factors. In the Metabolic Syndrome and Cancer project (Me-Can) data on body mass index (BMI, kg/m2), blood pressure, and circulating levels of glucose, cholesterol, and triglycerides were collected from 560,388 men and women in cohorts from Norway, Austria, and Sweden. By use of Cox proportional hazard models, hazard ratios (HR) were calculated for separate and composite metabolic exposures. During a median follow-up of 10 years, 592 men and 263 women were diagnosed with RCC. Among men, we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 1.51, 95% CI 1.13-2.03), systolic blood pressure, (HR = 3.40, 95% CI 1.91-6.06), diastolic blood pressure, (HR = 3.33, 95% CI 1.85-5.99), glucose, (HR = 3.75, 95% CI 1.46-9.68), triglycerides, (HR = 1.79, 95% CI 1.00-3.21) and a composite score of these metabolic factors, (HR = 2.68, 95% CI 1.75-4.11). Among women we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 2.21, 95% CI 1.32-3.70) and the composite score, (HR = 2.29, 95% CI 1.12-4.68). High levels of the composite score were also associated with risk of death from RCC among both men and women. No multiplicative statistical or biological interactions between metabolic factors on risk of RCC were found. High levels of BMI, blood pressure, glucose and triglycerides among men and high BMI among women were associated with increased risk of RCC.

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