Association of NOS1AP genetic variants with QT interval duration in families from the Diabetes Heart Study.
OBJECTIVE
Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes-enriched sample of European ancestry.


METHODS
Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.


RESULTS
In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 x 10(-5)); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 x 10(-6)). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 x 10(-5); 13.9-ms difference, P = 1.6 x 10(-6), respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans.


CONCLUSIONS
Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.
Lehtinen
Allison B
AB
Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Newton-Cheh
Christopher
C
Ziegler
Julie T
JT
Langefeld
Carl D
CD
Freedman
Barry I
BI
Daniel
Kurt R
KR
Herrington
David M
DM
Bowden
Donald W
DW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D044383:Black People / Q000235:genetics; D015992:Body Mass Index; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D044465:White People / Q000235:genetics; D001741:Black or African American
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D004247:DNA