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  • 1. Ali, Ashfaq
    et al.
    Varga, Tibor V.
    Stojkovic, Ivana A.
    Schulz, Christina-Alexandra
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Barroso, Ines
    Poveda, Alaitz
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Orho-Melander, Marju
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?: Findings From the GLACIER and the MDC Studies2016In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 2, p. 162-171Article in journal (Refereed)
    Abstract [en]

    Background Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability.

    Methods and Results We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmo Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS(TG)) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS(TG) were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4x10(-84)) higher triglyceride concentration and each additional WGRS(TG) unit with 2% (P=7.6x10(-48)) higher triglyceride concentration. Each unit of the WGRS(TG) was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (P-interaction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS(TG)xBMI interaction effect (P-interaction=6.0x10(-4)), which was strengthened by including data from the Danish cohorts (P-interaction=6.5x10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS(TG)xBMIxsex) was observed (P-interaction=0.03), where the WGRS(TG)xBMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci.

    Conclusions Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.

  • 2.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jansson, Jan-Håkan
    Medicinkliniken, Skellefteå lasarett.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting2010In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, no 3, p. 340-347Article in journal (Refereed)
    Abstract [en]

    Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting.

    Methods and Results: 618 subjects with a first-ever myocardial infarction (median event age 60.5 years, median lag time 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases vs. referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels.

    Conclusion: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation or increased elimination.

  • 3.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jansson, Jan-Håkan
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Response to letter regarding article "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective nested case-referent setting"2011In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, no 1, p. e2-Article in journal (Refereed)
  • 4. Kraja, Aldi T.
    et al.
    Cook, James P.
    Warren, Helen R.
    Surendran, Praveen
    Liu, Chunyu
    Evangelou, Evangelos
    Manning, Alisa K.
    Grarup, Niels
    Drenos, Fotios
    Sim, Xueling
    Smith, Albert Vernon
    Amin, Najaf
    Blakemore, Alexandra I. F.
    Bork-Jensen, Jette
    Brandslund, Ivan
    Farmaki, Aliki-Eleni
    Fava, Cristiano
    Ferreira, Teresa
    Herzig, Karl-Heinz
    Giri, Ayush
    Giulianini, Franco
    Grove, Megan L.
    Guo, Xiuqing
    Harris, Sarah E.
    Have, Christian T.
    Havulinna, Aki S.
    Zhang, He
    Jorgensen, Marit E.
    Karajamaki, AnneMari
    Kooperberg, Charles
    Linneberg, Allan
    Little, Louis
    Liu, Yongmei
    Bonnycastle, Lori L.
    Lu, Yingchang
    Magi, Reedik
    Mahajan, Anubha
    Malerba, Giovanni
    Marioni, Riccardo E.
    Mei, Hao
    Menni, Cristina
    Morrison, Alanna C.
    Padmanabhan, Sandosh
    Palmas, Walter
    Poveda, Alaitz
    Rauramaa, Rainer
    Rayner, Nigel William
    Riaz, Muhammad
    Rice, Ken
    Richard, Melissa A.
    Smith, Jennifer A.
    Southam, Lorraine
    Stancakova, Alena
    Stirrups, Kathleen E.
    Tragante, Vinicius
    Tuomi, Tiinamaija
    Umeå University, Faculty of Medicine, Department of Biobank Research. Folkhälsan Research Centre, Finland; Department of Endocrinology, Helsinki University Central Hospital, Finland; Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Finland.
    Tzoulald, Ioanna
    Varga, Tibor V.
    Weiss, Stefan
    Yiorkas, Andrianos M.
    Young, Robin
    Zhang, Weihua
    Barnes, Michael R.
    Cabrera, Claudia P.
    Gao, He
    Boehnke, Michael
    Boerwinkle, Eric
    Chambers, John C.
    Connell, John M.
    Christensen, Cramer K.
    de Boer, Rudolf A.
    Deary, Ian J.
    Dedoussis, George
    Deloukas, Panos
    Dominiczak, Anna F.
    Dorr, Marcus
    Joehanes, Roby
    Edwards, Todd L.
    Esko, Tonu
    Fornage, Myriam
    Franceschini, Nora
    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, MA, United States.
    Gambaro, Giovanni
    Groop, Leif
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hansen, Torben
    Hayward, Caroline
    Heikki, Oksa
    Ingelsson, Erik
    Tuomilehto, Jaakko
    Jarvelin, Marjo-Riitta
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kooner, Jaspal S.
    Lakka, Timo A.
    Langenberg, Claudia
    Lind, Lars
    Loos, Ruth J. F.
    Laakso, Markku
    McCarthy, Mark I.
    Melander, Olle
    Mohlke, Karen L.
    Moris, Andrwe P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Polasek, Ozren
    Poulter, Neil R.
    Province, Michael A.
    Psaty, Bruce M.
    Ridker, Paul M.
    Rotter, Jerome I.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Sever, Peter J.
    Skaaby, Tea
    Stafford, Jeanette M.
    Starr, John M.
    van der Harst, Pim
    van der Meer, Peter
    van Duijn, Cornelia M.
    Vergnaud, Anne-Claire
    Gudnason, Vilmundur
    Wareham, Nicholas J.
    Wilson, James G.
    Willer, Cristen J.
    Witte, Daniel R.
    Zeggini, Eleftheria
    Saleheen, Danish
    Butterworth, Adam S.
    Danesh, John
    Asselbergs, Folkert W.
    Wain, Louise V.
    Ehret, Georg B.
    Chasman, Daniel I.
    Caulfield, Mark J.
    Elliott, Paul
    Lindgren, Cecilia M.
    Levy, Daniel
    Newton-Cheh, Christopher
    Munroe, Patricia B.
    Howson, Joanna M. M.
    New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 5, article id e001778Article in journal (Refereed)
    Abstract [en]

    Background-Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. & para;& para;Methods and Results-Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.& para;& para;Conclusions-We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

  • 5. Leonard, Dag
    et al.
    Svenungsson, Elisabet
    Sandling, Johanna K.
    Berggren, Olof
    Jönsen, Andreas
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wang, Chuan
    Jensen-Urstad, Kerstin
    Granstam, Sven-Olof
    Bengtsson, Anders A.
    Gustafsson, Johanna T.
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Syvänen, Ann-Christine
    Rönnblom, Lars
    Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants2013In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 6, no 3, p. 255-263Article in journal (Refereed)
    Abstract [en]

    Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9x10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.

  • 6. Varga, Tibor V.
    et al.
    Winters, Alexandra H.
    Jablonski, Kathleen A.
    Horton, Edward S.
    Khare-Ranade, Prajakta
    Knowler, William C.
    Marcovina, Santica M.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Watson, Karol E.
    Goldberg, Ronald
    Florez, José C.
    Pollin, Toni I.
    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, MA.
    Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program2016In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 6, p. 495-503Article in journal (Refereed)
    Abstract [en]

    Background: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.

  • 7. Wild, Philipp S.
    et al.
    Zeller, Tanja
    Schillert, Arne
    Szymczak, Silke
    Sinning, Christoph R.
    Deiseroth, Arne
    Schnabel, Renate B.
    Lubos, Edith
    Keller, Till
    Eleftheriadis, Medea S.
    Bickel, Christoph
    Rupprecht, Hans J.
    Wilde, Sandra
    Rossmann, Heidi
    Diemert, Patrick
    Cupples, L. Adrienne
    Perret, Claire
    Erdmann, Jeanette
    Stark, Klaus
    Kleber, Marcus E.
    Epstein, Stephen E.
    Voight, Benjamin F.
    Kuulasmaa, Kari
    Li, Mingyao
    Schaefer, Arne S.
    Klopp, Norman
    Braund, Peter S.
    Sager, Hendrik
    Demissie, Serkalem
    Proust, Carole
    Koenig, Inke R.
    Wichmann, Heinz-Erich
    Reinhard, Wibke
    Hoffmann, Michael M.
    Virtamo, Jarmo
    Burnett, Mary Susan
    Siscovick, David
    Wiklund, Per Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Qu, Liming
    El Mokthari, Nour Eddine
    Thompson, John R.
    Peters, Annette
    Smith, Albert V.
    Yon, Emmanuelle
    Baumert, Jens
    Hengstenberg, Christian
    Maerz, Winfried
    Amouyel, Philippe
    Devaney, Joseph
    Schwartz, Stephen
    Saarela, Olli
    Mehta, Nehal N.
    Rubin, Diana
    Silander, Kaisa
    Hall, Alistair S.
    Ferriers, Jean
    Harris, Tamara B.
    Melander, Olle
    Kee, Frank
    Hakonarson, Hakon
    Schrezenmeir, Juergen
    Gudnason, Vilmundur
    Elosua, Roberto
    Arveiler, Dominique
    Evans, Alun
    Rader, Daniel J.
    Illig, Thomas
    Schreiber, Stefan
    Bis, Joshua C.
    Altshuler, David
    Kavousi, Maryam
    Witteman, Jaqueline C. M.
    Uitterlinden, Andre G.
    Hofman, Albert
    Folsom, Aaron R.
    Barbalic, Maja
    Boerwinkle, Eric
    Kathiresan, Sekar
    Reilly, Muredach P.
    O'Donnell, Christopher J.
    Samani, Nilesh J.
    Schunkert, Heribert
    Cambien, Francois
    Lackner, Karl J.
    Tiret, Laurence
    Salomaa, Veikko
    Munzel, Thomas
    Ziegler, Andreas
    Blankenberg, Stefan
    A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease2011In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, no 4, p. 403-412Article in journal (Refereed)
    Abstract [en]

    Background: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).

    Methods and Results: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)).

    Conclusions: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)

  • 8.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population2009In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 2, no 6, p. 558-564Article in journal (Refereed)
    Abstract [en]

    Background: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events.

    Methods and Results: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers <40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25±20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, P=0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (n=24) and family members (n=83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915.

    Conclusions: The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome.

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