Abstract 2924: Association of
            NOS1AP
            Genetic Variants with QT Interval Duration in Families from the Diabetes Heart Study

Background: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD) in unselected samples as well as in post-myocardial infarction patients or those with diabetes. Common genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene have been reported to be associated with QT interval duration in individuals of European ancestry. We sought to replicate the association of NOS1AP variants with QT interval duration in pedigrees enriched for type 2 diabetes mellitus (T2DM). Methods and Results: Two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 and rs10918594, were genotyped in a collection of 937 European Americans (EAs) and 177 African Americans (AAs) in 450 pedigrees containing at least two siblings with T2DM. An additive genetic model was tested for each SNP in ancestry-specific analyses using SOLAR in the total sample and in the diabetic subset (EA n=778, AA n=159), with and without exclusion of QT-altering medications. In the EA individuals, rs10494366 minor allele homozygotes had an 8.9 msec longer mean QT interval compared to major homozygotes (additive model p=4.4x10 -3 ); rs10918594 minor homozygotes had a 12.9 msec longer mean QT interval compared to major homozygotes (p=9.9x10 -5 ). Excluding users of QT-altering medications in the diabetic-only EA sample (n=514) strengthened the association despite the reduction in sample size (20.6 msec difference, p=2.0x10 -5 ; 23.4 msec difference, p=8.9x10 -7 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AA individuals examined. Conclusions: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic EA sample. Stronger effects of NOS1AP variants in diabetic individuals compared to previously reported unselected samples suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

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Abstract 4401: Two Independent Genetic Variants in NOS1AP are Associated with QT interval in a Multi-Ethnic Population: the Dallas Heart Study

Circulation ◽

10.1161/circ.118.suppl_18.s_882 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Dan E Arking ◽

Amit Khera ◽

Chao Xing ◽

Wen H Kao ◽

Aravinda Chakravarti

Keyword(s):

Heart Rate ◽

Genetic Variants ◽

Qt Interval ◽

Genetic Model ◽

Black Population ◽

European Ancestry ◽

Ethnic Population ◽

Heart Study ◽

Increased Risk ◽

Dallas Heart Study

Extremes of QT interval are associated with increased risk for sudden cardiac death (SCD), and thus identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous work 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 thus sought to characterize the effects of NOS1AP genetic variants in the multi-ethnic population-based Dallas Heart Study (DHS). Among 3,557 participants in DHS with available DNA, those without QT interval, heart rate, age, and/or sex information, and those with QRS >120 or undetermined ethnicity were excluded, resulting in 2,949 samples available for analysis (501 Hispanic, 1,506 Black, 942 White). Sex- and ethnicity-stratified linear regression was used to correct QT interval for heart rate and age. Eight SNPs spanning the region previously associated with QT interval were genotyped, and ethnic-specific analyses were performed under an additive genetic model. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in the White participants (+2.6 ms, P<0.005) as well as in Blacks (+3.2 ms, P<3.6 × 10 –5), with the same direction of effect in Hispanics (+1.5 ms, P<0.17). A second SNP, rs16856785, which was uncorrelated with rs16847548 (r2 < 0.01 in Blacks) was also associated with QT interval in Blacks (+1.6 ms, P<0.01), with qualitatively similar results in Whites (+0.9 ms, P<0.33) and Hispanics (+0.6 ms, P<0.66). Adjusting for local and global ancestry using Ancestry Informative Markers did not significantly alter the results. Comparing Blacks homozygous at both SNPs for the QT lengthening allele to Blacks homozygous for the complementary alleles revealed a 13.9 ms difference in QT interval. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends in Hispanics. Further, a second, independent site within NOS1AP has been implicated in modulating QT interval, highlighting the importance of NOS1AP genetic variants in regulating QT interval.

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Relationship between Genetic Variants in Myocardial Sodium and Potassium Channel Genes and QT Interval Duration in Diabetics: The Diabetes Heart Study

Annals of Noninvasive Electrocardiology ◽

10.1111/j.1542-474x.2008.00276.x ◽

2009 ◽

Vol 14 (1) ◽

pp. 72-79 ◽

Cited By ~ 8

Author(s):

Allison B. Lehtinen ◽

Kurt R. Daniel ◽

Sidharth A. Shah ◽

Matthew R. Nelson ◽

Julie T. Ziegler ◽

...

Keyword(s):

Potassium Channel ◽

Genetic Variants ◽

Qt Interval ◽

Interval Duration ◽

Heart Study ◽

Diabetes Heart Study ◽

Qt Interval Duration ◽

Sodium And Potassium

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Associations between NOS1AP Single Nucleotide Polymorphisms (SNPs) and QT Interval Duration in Four Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis (MESA)

Annals of Noninvasive Electrocardiology ◽

10.1111/anec.12028 ◽

2013 ◽

Vol 18 (1) ◽

pp. 29-40 ◽

Cited By ~ 6

Author(s):

Sidharth A. Shah ◽

David M. Herrington ◽

Timothy D. Howard ◽

Jasmin Divers ◽

Donna K. Arnett ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Ethnic Groups ◽

Qt Interval ◽

Nucleotide Polymorphisms ◽

Interval Duration ◽

Single Nucleotide ◽

Ethnic Study ◽

Qt Interval Duration ◽

Racial Ethnic

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Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

Diabetes ◽

10.2337/db07-1365 ◽

2008 ◽

Vol 57 (4) ◽

pp. 1108-1114 ◽

Cited By ~ 40

Author(s):

A. B. Lehtinen ◽

C. Newton-Cheh ◽

J. T. Ziegler ◽

C. D. Langefeld ◽

B. I. Freedman ◽

...

Keyword(s):

Genetic Variants ◽

Qt Interval ◽

Interval Duration ◽

Heart Study ◽

Diabetes Heart Study ◽

Qt Interval Duration

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Faculty Opinions recommendation of Common variants at ten loci modulate the QT interval duration in the QTSCD Study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1161025.621483 ◽

2009 ◽

Author(s):

Pascale Guicheney ◽

Nathalie Neyroud

Keyword(s):

Qt Interval ◽

Interval Duration ◽

Common Variants ◽

Qt Interval Duration

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Faculty Opinions recommendation of Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4361959.4187057 ◽

2010 ◽

Author(s):

I Eli Ovsyshcher ◽

Guy Amit

Keyword(s):

Long Qt Syndrome ◽

Qt Interval ◽

Interval Duration ◽

Long Qt ◽

Qt Syndrome ◽

Qt Interval Duration

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Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins

Scientific Reports ◽

10.1038/s41598-021-86801-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sabrina Samad Shoily ◽

Tamim Ahsan ◽

Kaniz Fatema ◽

Abu Ashfaqur Sajib

Keyword(s):

Diabetes Mellitus ◽

Chronic Kidney Disease ◽

Genetic Variants ◽

Nucleotide Polymorphisms ◽

Differential Distribution ◽

East Asians ◽

Single Nucleotide ◽

Common Genetic Variants ◽

Haplotype Frequencies ◽

Variant Alleles

AbstractDiabetes mellitus is a complex and heterogeneous metabolic disorder which is often pre- or post-existent with complications such as cardiovascular disease, hypertension, inflammation, chronic kidney disease, diabetic retino- and nephropathies. However, the frequencies of these co-morbidities vary among individuals and across populations. It is, therefore, not unlikely that certain genetic variants might commonly contribute to these conditions. Here, we identified four single nucleotide polymorphisms (rs5186, rs1800795, rs1799983 and rs1800629 in AGTR1, IL6, NOS3 and TNFA genes, respectively) to be commonly associated with each of these conditions. We explored their possible interplay in diabetes and associated complications. The variant allele and haplotype frequencies at these polymorphic loci vary among different super-populations (African, European, admixed Americans, South and East Asians). The variant alleles are particularly highly prevalent in different European and admixed American populations. Differential distribution of these variants in different ethnic groups suggests that certain drugs might be more effective in selective populations rather than all. Therefore, population specific genetic architectures should be considered before considering a drug for these conditions.

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