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Fine-Mapping and Initial Characterization of QT Interval Loci in African Americans
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نویسنده
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avery c.l. ,sethupathy p. ,buyske s. ,he q. ,lin d.-y. ,arking d.e. ,carty c.l. ,duggan d. ,fesinmeyer m.d. ,hindorff l.a. ,jeff j.m. ,klein l. ,patton k.k. ,peters u. ,shohet r.v. ,sotoodehnia n. ,young a.m. ,kooperberg c. ,haiman c.a. ,mohlke k.l. ,whitsel e.a. ,north k.e.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 8
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چکیده
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The qt interval (qt) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. most genetic studies of qt have examined european ancestral populations; however,the increased genetic diversity in african americans provides opportunities to narrow association signals and identify population-specific variants. we therefore evaluated 6,670 snps spanning eleven previously identified qt loci in 8,644 african american participants from two population architecture using genomics and epidemiology (page) studies: the atherosclerosis risk in communities study and women's health initiative clinical trial. of the fifteen known independent qt variants at the eleven previously identified loci,six were significantly associated with qt in african american populations (p≤1.20×10-4): atp1b1,pln1,kcnq1,ndrg4,and two nos1ap independent signals. we also identified three population-specific signals significantly associated with qt in african americans (p≤1.37×10-5): one at nos1ap and two at atp1b1. linkage disequilibrium (ld) patterns in african americans assisted in narrowing the region likely to contain the functional variants for several loci. for example,african american ld patterns showed that 0 snps were in ld with nos1ap signal rs12143842,compared with european ld patterns that indicated 87 snps,which spanned 114.2 kb,were in ld with rs12143842. finally,bioinformatic-based characterization of the nine african american signals pointed to functional candidates located exclusively within non-coding regions,including predicted binding sites for transcription factors such as tbx5,which has been implicated in cardiac structure and conductance. in this detailed evaluation of qt loci,we identified several african americans snps that better define the association with qt and successfully narrowed intervals surrounding established loci. these results demonstrate that the same loci influence variation in qt across multiple populations,that novel signals exist in african americans,and that the snps identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in qt prolongation.
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آدرس
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department of epidemiology,university of north carolina at chapel hill,chapel hill,nc, United States, department of genetics,university of north carolina at chapel hill,chapel hill,nc,united states,carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc, United States, department of statistics and biostatistics,rutgers university,piscataway,nj,united states,department of genetics,rutgers university,piscataway,nj, United States, department of biostatistics,university of north carolina at chapel hill,chapel hill,nc, United States, department of biostatistics,university of north carolina at chapel hill,chapel hill,nc, United States, mckusick-nathans institute of genetic medicine and division of cardiology,department of medicine,johns hopkins university school of medicine,baltimore,md, United States, fred hutchinson cancer research center,seattle,wa, United States, translational genomics research institute,phoenix,az, United States, fred hutchinson cancer research center,seattle,wa, United States, office of population genomics,national human genome research institute,national institutes of health,bethesda,md, United States, department of medicine,vanderbilt university,nashville,tn, United States, department of medicine,university of california san francisco,san francisco,ca, United States, division of cardiology,university of washington,seattle,wa, United States, fred hutchinson cancer research center,seattle,wa, United States, center for cardiovascular research,john a. burns school of medicine,university of hawaii,honolulu,hi, United States, division of cardiology,university of washington,seattle,wa, United States, fred hutchinson cancer research center,seattle,wa, United States, fred hutchinson cancer research center,seattle,wa, United States, department of preventive medicine,keck school of medicine and norris comprehensive cancer center,university of southern california,pasadena,ca, United States, department of genetics,university of north carolina at chapel hill,chapel hill,nc,united states,carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc, United States, department of epidemiology,university of north carolina at chapel hill,chapel hill,nc,united states,department of medicine,university of north carolina at chapel hill,chapel hill,nc, United States, department of epidemiology,university of north carolina at chapel hill,chapel hill,nc,united states,carolina center for genome sciences,university of north carolina at chapel hill,chapel hill,nc, United States
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Authors
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