Common variants in cardiac ion channel genes are associated with sudden cardiac death.
BACKGROUND
Rare variants in cardiac ion channel genes are associated with sudden cardiac death in rare primary arrhythmic syndromes; however, it is unknown whether common variation in these same genes may contribute to sudden cardiac death risk at the population level.


RESULTS
We examined the association between 147 single nucleotide polymorphisms (SNPs) (137 tag, 5 noncoding SNPs associated with QT interval duration, and 5 nonsynonymous SNPs) in 5 cardiac ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, and sudden and/or arrhythmic death in a combined nested case-control analysis among 516 cases and 1522 matched control subjects of European ancestry enrolled in 6 prospective cohort studies. After accounting for multiple testing, 2 SNPs (rs2283222 located in intron 11 in KCNQ1 and rs11720524 located in intron 1 in SCN5A) remained significantly associated with sudden/arrhythmic death (false discovery rate=0.01 and 0.03, respectively). Each increasing copy of the major T-allele of rs2283222 or the major C-allele of rs1172052 was associated with an odds ratio of 1.36 (95% confidence interval, 1.16 to 1.60; P=0.0002) and 1.30 (95% confidence interval, 1.12 to 1.51; P=0.0005), respectively. Control for cardiovascular risk factors and/or limiting the analysis to definite sudden cardiac death did not significantly alter these relationships.


CONCLUSIONS
In this combined analysis of 6 prospective cohort studies, 2 common intronic variants in KCNQ1 and SCN5A were associated with sudden cardiac death in individuals of European ancestry. Further study in other populations and investigation into the functional abnormalities associated with noncoding variation in these genes may lead to important insights into predisposition to lethal arrhythmias.
Albert
Christine M
CM
Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Channing Laboratory, and Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-1204, USA. calbert@partners.org
MacRae
Calum A
CA
Chasman
Daniel I
DI
VanDenburgh
Martin
M
Buring
Julie E
JE
Manson
JoAnn E
JE
Cook
Nancy R
NR
Newton-Cheh
Christopher
C
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D016757:Death, Sudden, Cardiac / Q000208:ethnology / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D013997:Time Factors; D044465:White People / Q000235:genetics
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels
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