Item Details

title

The Association of Single Nucleotide Polymorphisms (SNPs) in the Nitric Oxide Synthase 1 Adaptor Protein Gene (NOS1AP) and the QT Interval Duration Across Race/Ethnicity in Adults Without Clinical Cardiovascular Disease

author

Shah, Sidharth

abstract

Introduction: The QT interval is an independent risk factor for sudden cardiac death (SCD). A genome wide association study (GWAS) identified NOS1AP variants associated with QT, which has been replicated in predominantly Caucasian populations. The MESA study provides an opportunity to study single nucleotide polymorphisms (SNPs) in NOS1AP for association with QT interval in an ethnically diverse cohort. Methods: Twenty-eight tagging SNPs, starting in the first intron and spanning the entire gene, were genotyped in 2847 men and women, age 45- 84 years, without known CVD in MESA, including approximately equal numbers of Caucasians (CAU), African-Americans (AFA) , Hispanics (HIS) and Chinese (CHN) US participants. QT interval was determined using a standard 12-lead ECG recording. Associations between QT and genotypes were evaluated using multiple linear regression, adjusted for heart rate (HR), age, gender, and field center stratified by racial/ethnic group, using an additive model of inheritance. Ancestry informative markers (AIMs) were genotyped in MESA participants and principal components (PCs) using AIMs were used as additional covariates in accounting for population stratification (PS). Results: Associations between genotype and QT interval were stronger in CAU (11 SNPs, p=7.20x10-7- 4.3x10-2) than in AFA (2 SNPs, p=0.030- 0.043), CHN (5 SNPs, p=0.021- 0.047) or HIS (3 SNPs, p= 0.03- 0.003). In CAU, each additional copy of the minor allele in rs1932933 was associated with a 4.5 msec increase in QT (p= 7.20x10-7). The preponderance of significant CAU and HIS SNPs were at the 5’ end of NOS1AP (some within similar LD blocks), while significant associations in CHN were only at the 3’ end. Conclusions: NOS1AP variants are associated with QT interval in AFA, CAU, HIS, and CHN. The location of significant SNPs varies across racial/ethnic groups. We have identified possible novel variants at the 3’ end of NOS1AP associated with QT in CHN only. Further genotyping within these regions should be pursued to determine functional genetic variants affecting QT interval and the potential risk for SCD.

subject

NOS1AP

Genetics

QT interval

Electrophysiology

MESA

Cardiology

race

Genetic Epidemiology

contributor

Bowden, Donald (committee chair)

Herrington, David (committee member)

Case, Doug (committee member)

Howard, Timothy (committee member)

date

2010-05-14T20:15:11Z (accessioned)

2010-06-18T18:59:50Z (accessioned)

2010-05-14T20:15:11Z (available)

2010-06-18T18:59:50Z (available)

2010-05-14T20:15:11Z (issued)

degree

Clinical Epidemiology & Health Services (discipline)

identifier

http://hdl.handle.net/10339/14897 (uri)

language

en (iso)

publisher

Wake Forest University

rights

Release the entire work immediately for access worldwide. (accessRights)

type

Thesis