Multiple independent Genetic Factors at Nos1Ap Modulate the Qt interval in a Multi-Ethnic Population

Authors

Dan E. Arking, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Amit Khera, Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
Chao Xing, McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
W H Linda Kao, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
Wendy Post, Department of Medicine, Johns Hopkins University School of Medicine
Eric Boerwinkle, Human Genetics Center and Division of Epidemiology, The University of Texas, Houston, Texas, United States of AmericaFollow
Aravinda Chakravarti, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

Publication Date

1-30-2009

Journal

PLoS ONE

Abstract

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

Keywords

Adaptor Proteins, Signal Transducing, Adolescent, Adult, African Americans, Aged, Death, Sudden, Cardiac, Electrocardiography, Ethnic Groups, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heart Diseases, Heart Rate, Hispanic Americans, Humans, Linear Models, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Sex Factors, Young Adult

Comments

PMCID: PMC2628730

Link to article in PLoS