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A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization


Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

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Figure 1: Genome-wide association study of the QT interval.
Figure 2: Genome-wide significance of QTc_RAS.
Figure 3: Fine mapping of the NOS1AP gene.

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The authors wish to thank G. Tomaselli, J. Nathans, S. Lin and D.J. Cutler for numerous helpful discussions and D. Levy, E. Benjamin and R. D'Agostino at FHS for contributions to the electrocardiographic QT measurement study. This work was supported in part by the D.W. Reynolds Clinical Cardiovascular Research Center, Johns Hopkins University, the US National Institutes of Health, and the German Federal Ministry of Education and Research (BMBF) both in the context of the program Bioinformatics for the Functional Analysis of Mammalian Genomes (BFAM) and the German National Genome Research Network (NGFN). The authors want to thank H. Löwel, C. Meisinger, R. Holle and J. John from the KORA Study Group. The FHS replication study is a contribution from the Framingham Heart Study of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and Boston University School of Medicine, supported by NHLBI's Framingham Heart Study (Contract No. N01-HC-25195) and the Cardiogenomics Program for Genomic Applications (5U01HL066582), a GlaxoSmithKline Competitive Grants Award Program for Young Investigators (CNC) and NIH (K23HL080025, CNC). Some of the electrocardiographic measurements were supported by an unrestricted grant from Pfizer, Inc.

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Correspondence to Aravinda Chakravarti.

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A.C. is a paid member of the Affymetrix Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Supplementary information

Supplementary Table 1

Summary of stage I results stratified by short and long QT interval. (PDF 90 kb)

Supplementary Table 2

Candidate gene list and SNP coverage on Affymetrix Centurion arrays. (PDF 42 kb)

Supplementary Table 3

Genome-wide association study of QTc_RAS: screening results from stages I and II. (PDF 140 kb)

Supplementary Table 4

Association study of QTc_RAS emphasizing candidate genes assayed genome-wide: screening results from stages I and II. (PDF 140 kb)

Supplementary Table 5

Significance of additional CAPON SNPs in the entire KORA S4 sample. (PDF 137 kb)

Supplementary Table 6

Sequenom SNP primers, probes and conditions. (PDF 65 kb)

Supplementary Table 7

Primers used in sequencing conserved regions in CAPON. (PDF 10 kb)

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Arking, D., Pfeufer, A., Post, W. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 38, 644–651 (2006).

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