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  • 1. Ahmad, Shafqat
    et al.
    Rukh, Gull
    Varga, Tibor V
    Ali, Ashfaq
    Kurbasic, Azra
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Lund University.
    Ericson, Ulrika
    Koivula, Robert W
    Chu, Audrey Y
    Rose, Lynda M
    Ganna, Andrea
    Qi, Qibin
    Stancakova, Alena
    Sandholt, Camilla H
    Elks, Cathy E
    Curhan, Gary
    Jensen, Majken K
    Tamimi, Rulla M
    Allin, Kristine H
    Jorgensen, Torben
    Brage, Soren
    Langenberg, Claudia
    Aadahl, Mette
    Grarup, Niels
    Linneberg, Allan
    Pare, Guillaume
    Magnusson, Patrik KE
    Pedersen, Nancy L
    Boehnke, Michael
    Hamsten, Anders
    Mohlke, Karen L
    Pasquale, Louis T
    Pedersen, Oluf
    Scott, Robert A
    Ridker, Paul M
    Ingelsson, Erik
    Laakso, Markku
    Hansen, Torben
    Qi, Lu
    Wareham, Nicholas J
    Chasman, Daniel I
    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.
    Hu, Frank B
    Renström, Frida
    Orho-Melander, Marju
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund University and Harvard University.
    Gene x physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 7, p. e1003607-Article in journal (Refereed)
    Abstract [en]

    Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS x physical activity interaction effect estimate (P-interaction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, P-interaction = 0.014 vs. n = 71,611, P-interaction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (P-interaction = 0.003) and the SEC16B rs10913469 (P-interaction = 0.025) variants showed evidence of SNP x physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

  • 2.
    Buckland, Robert J
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Watt, Danielle L
    Chittoor, Balasubramanyam
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kunkel, Thomas A
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, article id e1004846Article in journal (Refereed)
    Abstract [en]

    The fidelity of DNA replication requires an appropriate balance of dNTPs, yet the nascent leading and lagging strands of the nuclear genome are primarily synthesized by replicases that differ in subunit composition, protein partnerships and biochemical properties, including fidelity. These facts pose the question of whether imbalanced dNTP pools differentially influence leading and lagging strand replication fidelity. Here we test this possibility by examining strand-specific replication infidelity driven by a mutation in yeast ribonucleotide reductase, rnr1-Y285A, that leads to elevated dTTP and dCTP concentrations. The results for the CAN1 mutational reporter gene present in opposite orientations in the genome reveal that the rates, and surprisingly even the sequence contexts, of replication errors are remarkably similar for leading and lagging strand synthesis. Moreover, while many mismatches driven by the dNTP pool imbalance are efficiently corrected by mismatch repair, others are repaired less efficiently, especially those in sequence contexts suggesting reduced proofreading due to increased mismatch extension driven by the high dTTP and dCTP concentrations. Thus the two DNA strands of the nuclear genome are at similar risk of mutations resulting from this dNTP pool imbalance, and this risk is not completely suppressed even when both major replication error correction mechanisms are genetically intact.

  • 3. Dörr, Tobias
    et al.
    Lam, Hubert
    Alvarez, Laura
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Davis, Brigid M.
    Waldor, Matthew K.
    A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004433-Article in journal (Refereed)
    Abstract [en]

    The bacterial cell wall, which is comprised of a mesh of polysaccharide strands crosslinked via peptide bridges (peptidoglycan, PG), is critical for maintenance of cell shape and survival. PG assembly is mediated by a variety of Penicillin Binding Proteins (PBP) whose fundamental activities have been characterized in great detail; however, there is limited knowledge of the factors that modulate their activities in different environments or growth phases. In Vibrio cholerae, the cause of cholera, PG synthesis during the transition into stationary phase is primarily mediated by the bifunctional enzyme PBP1A. Here, we screened an ordered V. cholerae transposon library for mutants that are sensitive to growth inhibition by non-canonical D-amino acids (DAA), which prevent growth and maintenance of cell shape in PBP1A-deficient V. cholerae. In addition to PBP1A and its lipoprotein activator LpoA, we found that CsiV, a small periplasmic protein with no previously described function, is essential for growth in the presence of DAA. Deletion of csiV, like deletion of lpoA or the PBP1A-encoding gene mrcA, causes cells to lose their rod shape in the presence of DAA or the beta-lactam antibiotic cefsulodin, and all three mutations are synthetically lethal with deletion of mrcB, which encodes PBP1B, V. cholerae's second key bifunctional PBP. CsiV interacts with LpoA and PG but apparently not with PBP1A, supporting the hypothesis that CsiV promotes LpoA's role as an activator of PBP1A, and thereby modulates V. cholerae PG biogenesis. Finally, the requirement for CsiV in PBP1A-mediated growth of V. cholerae can be overcome either by augmenting PG synthesis or by reducing PG degradation, thereby highlighting the importance of balancing these two processes for bacterial survival.

  • 4.
    Kahn, Tatyana G.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pirrotta, Vincenzo
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Combinatorial Interactions Are Required for the Efficient Recruitment of Pho Repressive Complex (PhoRC) to Polycomb Response Elements2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 7, p. e1004495-Article in journal (Refereed)
    Abstract [en]

    Polycomb Group (PcG) proteins are epigenetic repressors that control metazoan development and cell differentiation. In Drosophila, PcG proteins form five distinct complexes targeted to genes by Polycomb Response Elements (PREs). Of all PcG complexes PhoRC is the only one that contains a sequence-specific DNA binding subunit (PHO or PHOL), which led to a model that places PhoRC at the base of the recruitment hierarchy. Here we demonstrate that in vivo PHO is preferred to PHOL as a subunit of PhoRC and that PHO and PHOL associate with PREs and a subset of transcriptionally active promoters. Although the binding to the promoter sites depends on the quality of recognition sequences, the binding to PREs does not. Instead, the efficient recruitment of PhoRC to PREs requires the SFMBT subunit and crosstalk with Polycomb Repressive Complex 1. We find that human YY1 protein, the ortholog of PHO, binds sites at active promoters in the human genome but does not bind most PcG target genes, presumably because the interactions involved in the targeting to Drosophila PREs are lost in the mammalian lineage. We conclude that the recruitment of PhoRC to PREs is based on combinatorial interactions and propose that such a recruitment strategy is important to attenuate the binding of PcG proteins when the target genes are transcriptionally active. Our findings allow the appropriate placement of PhoRC in the PcG recruitment hierarchy and provide a rationale to explain why YY1 is unlikely to serve as a general recruiter of mammalian Polycomb complexes despite its reported ability to participate in PcG repression in flies.

  • 5. Lin, Chia-Yeh
    et al.
    Wu, Meng-Ying
    Gay, Sophie
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lai, Mong Sing
    Hsiao, Wei-Chun
    Hung, Shih-Hsun
    Tseng, Hsin-Yi
    Wright, Duncan Edward
    Wang, Chen-Yi
    Hsu, Guoo-Shyng W
    Devys, Didier
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kao, Cheng-Fu
    H2B Mono-ubiquitylation Facilitates Fork Stalling and Recovery during Replication Stress by Coordinating Rad53 Activation and Chromatin Assembly2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 10, p. e1004667-Article in journal (Refereed)
    Abstract [en]

    The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression.

  • 6. Lutz, Ulrich
    et al.
    Posé, David
    Pfeifer, Matthias
    Gundlach, Heidrun
    Hagmann, Jörg
    Wang, Congmao
    Weigel, Detlef
    Mayer, Klaus F. X.
    Schmid, Markus
    Max Planck Institute for Developmental Biology, Department of Molecular Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
    Schwechheimer, Claus
    Modulation of Ambient Temperature-Dependent Flowering in Arabidopsis thaliana by Natural Variation of FLOWERING LOCUS M2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 10, article id e1005588Article in journal (Refereed)
    Abstract [en]

    Plants integrate seasonal cues such as temperature and day length to optimally adjust their flowering time to the environment. Compared to the control of flowering before and after winter by the vernalization and day length pathways, mechanisms that delay or promote flowering during a transient cool or warm period, especially during spring, are less well understood. Due to global warming, understanding this ambient temperature pathway has gained increasing importance. In Arabidopsis thalianaFLOWERING LOCUS M (FLM) is a critical flowering regulator of the ambient temperature pathway. FLM is alternatively spliced in a temperature-dependent manner and the two predominant splice variants, FLM-ß and FLM-δ, can repress and activate flowering in the genetic background of the Athaliana reference accession Columbia-0. The relevance of this regulatory mechanism for the environmental adaptation across the entire range of the species is, however, unknown. Here, we identify insertion polymorphisms in the first intron of FLM as causative for accelerated flowering in many natural A. thaliana accessions, especially in cool (15°C) temperatures. We present evidence for a potential adaptive role of this structural variation and link it specifically to changes in the abundance of FLM-ß. Our results may allow predicting flowering in response to ambient temperatures in the Brassicaceae.

  • 7. McKay, James D.
    et al.
    Truong, Therese
    Gaborieau, Valerie
    Chabrier, Amelie
    Chuang, Shu-Chun
    Byrnes, Graham
    Zaridze, David
    Shangina, Oxana
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Bucur, Alexandru
    Bencko, Vladimir
    Holcatova, Ivana
    Janout, Vladimir
    Foretova, Lenka
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Benhamou, Simone
    Bouchardy, Christine
    Ahrens, Wolfgang
    Merletti, Franco
    Richiardi, Lorenzo
    Talamini, Renato
    Barzan, Luigi
    Kjaerheim, Kristina
    Macfarlane, Gary J.
    Macfarlane, Tatiana V.
    Simonato, Lorenzo
    Canova, Cristina
    Agudo, Antonio
    Castellsague, Xavier
    Lowry, Ray
    Conway, David I.
    McKinney, Patricia A.
    Healy, Claire M.
    Toner, Mary E.
    Znaor, Ariana
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wuensch-Filho, Victor
    Neto, Jose Eluf
    Fernandez Garrote, Leticia
    Boccia, Stefania
    Cadoni, Gabriella
    Arzani, Dario
    Olshan, Andrew F.
    Weissler, Mark C.
    Funkhouser, William K.
    Luo, Jingchun
    Lubinski, Jan
    Trubicka, Joanna
    Lener, Marcin
    Oszutowska, Dorota
    Schwartz, Stephen M.
    Chen, Chu
    Fish, Sherianne
    Doody, David R.
    Muscat, Joshua E.
    Lazarus, Philip
    Gallagher, Carla J.
    Chang, Shen-Chih
    Zhang, Zuo-Feng
    Wei, Qingyi
    Sturgis, Erich M.
    Wang, Li-E
    Franceschi, Silvia
    Herrero, Rolando
    Kelsey, Karl T.
    McClean, Michael D.
    Marsit, Carmen J.
    Nelson, Heather H.
    Romkes, Marjorie
    Buch, Shama
    Nukui, Tomoko
    Zhong, Shilong
    Lacko, Martin
    Manni, Johannes J.
    Peters, Wilbert H. M.
    Hung, Rayjean J.
    McLaughlin, John
    Vatten, Lars
    Njolstad, Inger
    Goodman, Gary E.
    Field, John K.
    Liloglou, Triantafillos
    Vineis, Paolo
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Gonzalez, Carlos A.
    Ramon Quiros, J.
    Martinez, Carmen
    Navarro, Carmen
    Ardanaz, Eva
    Larranaga, Nerea
    Khaw, Kay-Tee
    Key, Timothy
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Trichopoulou, Antonia
    Linseisen, Jakob
    Boeing, Heiner
    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.
    Overvad, Kim
    Tjonneland, Anne
    Kumle, Merethe
    Riboli, Elio
    Vaelk, Kristjan
    Voodern, Tonu
    Metspalu, Andres
    Zelenika, Diana
    Boland, Anne
    Delepine, Marc
    Foglio, Mario
    Lechner, Doris
    Blanche, Helene
    Gut, Ivo G.
    Galan, Pilar
    Heath, Simon
    Hashibe, Mia
    Hayes, Richard B.
    Boffetta, Paolo
    Lathrop, Mark
    Brennan, Paul
    A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium2011In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 3, article id e1001333Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  • 8. Miralles Fusté, Javier
    et al.
    Shi, Yonghong
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zhu, Xuefeng
    Jemt, Elisabeth
    Persson, Orjan
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gustafsson, Claes M
    Falkenberg, Maria
    In vivo occupancy of mitochondrial single-stranded DNA binding protein supports the strand displacement mode of DNA replication2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004832-Article in journal (Refereed)
    Abstract [en]

    Mitochondrial DNA (mtDNA) encodes for proteins required for oxidative phosphorylation, and mutations affecting the genome have been linked to a number of diseases as well as the natural ageing process in mammals. Human mtDNA is replicated by a molecular machinery that is distinct from the nuclear replisome, but there is still no consensus on the exact mode of mtDNA replication. We here demonstrate that the mitochondrial single-stranded DNA binding protein (mtSSB) directs origin specific initiation of mtDNA replication. MtSSB covers the parental heavy strand, which is displaced during mtDNA replication. MtSSB blocks primer synthesis on the displaced strand and restricts initiation of light-strand mtDNA synthesis to the specific origin of light-strand DNA synthesis (OriL). The in vivo occupancy profile of mtSSB displays a distinct pattern, with the highest levels of mtSSB close to the mitochondrial control region and with a gradual decline towards OriL. The pattern correlates with the replication products expected for the strand displacement mode of mtDNA synthesis, lending strong in vivo support for this debated model for mitochondrial DNA replication.

  • 9. Riddle, Nicole C
    et al.
    Jung, Youngsook L
    Gu, Tingting
    Alekseyenko, Artyom A
    Asker, Dalal
    Gui, Hongxing
    Kharchenko, Peter V
    Minoda, Aki
    Plachetka, Annette
    Schwartz, Yuri B
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Tolstorukov, Michael Y
    Kuroda, Mitzi I
    Pirrotta, Vincenzo
    Karpen, Gary H
    Park, Peter J
    Elgin, Sarah CR
    Enrichment of HP1a on drosophila chromosome 4 genes creates an alternate chromatin structure critical for regulation in this heterochromatic domain2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 9, p. e1002954-Article in journal (Refereed)
    Abstract [en]

    Chromatin environments differ greatly within a eukaryotic genome, depending on expression state, chromosomal location, and nuclear position. In genomic regions characterized by high repeat content and high gene density, chromatin structure must silence transposable elements but permit expression of embedded genes. We have investigated one such region, chromosome 4 of Drosophila melanogaster. Using chromatin-immunoprecipitation followed by microarray (ChIP-chip) analysis, we examined enrichment patterns of 20 histone modifications and 25 chromosomal proteins in S2 and BG3 cells, as well as the changes in several marks resulting from mutations in key proteins. Active genes on chromosome 4 are distinct from those in euchromatin or pericentric heterochromatin: while there is a depletion of silencing marks at the transcription start sites (TSSs), HP1a and H3K9me3, but not H3K9me2, are enriched strongly over gene bodies. Intriguingly, genes on chromosome 4 are less frequently associated with paused polymerase. However, when the chromatin is altered by depleting HP1a or POF, the RNA pol II enrichment patterns of many chromosome 4 genes shift, showing a significant decrease over gene bodies but not at TSSs, accompanied by lower expression of those genes. Chromosome 4 genes have a low incidence of TRL/GAGA factor binding sites and a low T-m downstream of the TSS, characteristics that could contribute to a low incidence of RNA polymerase pausing. Our data also indicate that EGG and POF jointly regulate H3K9 methylation and promote HP1a binding over gene bodies, while HP1a targeting and H3K9 methylation are maintained at the repeats by an independent mechanism. The HP1a-enriched, POF-associated chromatin structure over the gene bodies may represent one type of adaptation for genes embedded in repetitive DNA.

  • 10. Sandholm, Niina
    et al.
    Salem, Rany M.
    McKnight, Amy Jayne
    Brennan, Eoin P.
    Forsblom, Carol
    Isakova, Tamara
    McKay, Gareth J.
    Williams, Winfred W.
    Sadlier, Denise M.
    Makinen, Ville-Petteri
    Swan, Elizabeth J.
    Palmer, Cameron
    Boright, Andrew P.
    Ahlqvist, Emma
    Deshmukh, Harshal A.
    Keller, Benjamin J.
    Huang, Huateng
    Ahola, Aila J.
    Fagerholm, Emma
    Gordin, Daniel
    Harjutsalo, Valma
    He, Bing
    Heikkila, Outi
    Hietala, Kustaa
    Kyto, Janne
    Lahermo, Paivi
    Lehto, Markku
    Lithovius, Raija
    Osterholm, Anne-May
    Parkkonen, Maija
    Pitkaniemi, Janne
    Rosengard-Barlund, Milla
    Saraheimo, Markku
    Sarti, Cinzia
    Soderlund, Jenny
    Soro-Paavonen, Aino
    Syreeni, Anna
    Thorn, Lena M.
    Tikkanen, Heikki
    Tolonen, Nina
    Tryggvason, Karl
    Tuomilehto, Jaakko
    Waden, Johan
    Gill, Geoffrey V.
    Prior, Sarah
    Guiducci, Candace
    Mirel, Daniel B.
    Taylor, Andrew
    Hosseini, S. Mohsen
    Parving, Hans-Henrik
    Rossing, Peter
    Tarnow, Lise
    Ladenvall, Claes
    Alhenc-Gelas, Francois
    Lefebvre, Pierre
    Rigalleau, Vincent
    Roussel, Ronan
    Tregouet, David-Alexandre
    Maestroni, Anna
    Maestroni, Silvia
    Falhammar, Henrik
    Gu, Tianwei
    Mollsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cimponeriu, Danut
    Ioana, Mihai
    Mota, Maria
    Mota, Eugen
    Serafinceanu, Cristian
    Stavarachi, Monica
    Hanson, Robert L.
    Nelson, Robert G.
    Kretzler, Matthias
    Colhoun, Helen M.
    Panduru, Nicolae Mircea
    Gu, Harvest F.
    Brismar, Kerstin
    Zerbini, Gianpaolo
    Hadjadj, Samy
    Marre, Michel
    Groop, Leif
    Lajer, Maria
    Bull, Shelley B.
    Waggott, Daryl
    Paterson, Andrew D.
    Savage, David A.
    Bain, Stephen C.
    Martin, Finian
    Hirschhorn, Joel N.
    Godson, Catherine
    Florez, Jose C.
    Groop, Per-Henrik
    Maxwell, Alexander P.
    New susceptibility loci associated with kidney disease in type 1 diabetes2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 9, p. e1002921-Article in journal (Refereed)
    Abstract [en]

    Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

  • 11. Varga, Tibor V.
    et al.
    Sonestedt, Emily
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. 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.
    Koivula, Robert W.
    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.
    Andersson Escher, Stefan
    Barroso, Ines
    Nilsson, Peter
    Melander, Olle
    Orho-Melander, Marju
    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 Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden ; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004388-Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (beta = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0x10(-11) for TC; beta = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0x10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (beta = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0x10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (beta = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1x10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (beta = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4x10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P <= 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

  • 12. Yousefzadeh, Matthew J
    et al.
    Wyatt, David W
    Takata, Kei-Ichi
    Mu, Yunxiang
    Hensley, Sean C
    Tomida, Junya
    Bylund, Göran O
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Doublié, Sylvie
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ramsden, Dale A
    McBride, Kevin M
    Wood, Richard D
    Mechanism of suppression of chromosomal instability by DNA polymerase POLQ2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 10, p. e1004654-Article in journal (Refereed)
    Abstract [en]

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

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