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

  title={A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization},
  author={Dan E. Arking and Arne Pfeufer and Wendy S. Post and Wen Kao and Christopher Newton-Cheh and Morna A Ikeda and Kristen West and Carl S. Kashuk and Mahmut Akyol and Siegfried Perz and Shapour Jalilzadeh and Thomas Illig and Christian Gieger and Chao-Yu Guo and Martin G. Larson and H Erich Wichmann and Eduardo Marb{\'a}n and Christopher J. O’Donnell and Joel N. Hirschhorn and Stefan K{\"a}{\"a}b and Peter M. Spooner and Thomas Meitinger and Aravinda Chakravarti},
  journal={Nature Genetics},
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… 

Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration.

QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is approximately 35% heritable. In genome-wide association

University of Groningen Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation

A meta-analysis of three genome-wide association studies including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America found common variants near NOS1AP and the phospholamban gene were associated with QT interval.

Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study.

Additional evidence was provided for association between genetic variation within NOS1AP and SCD in the prospective population-based Rotterdam Study and the mechanism by which this effect is exerted remains to be elucidated.

Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population

The association of genetic variants in NOS1AP with QT interval to a Black population is extended, with similar trends, though not statistically significant at P<0.05, in Hispanics, and a strong sex-interaction and the presence of a second independent site within NOS 1AP associated with the QT intervals are identified.

Associations between Genetic Variants in the NOS1AP (CAPON) Gene and Cardiac Repolarization in the Old Order Amish

This study provides further evidence that NOS1AP variants influence QT interval and further validates the utility of genome-wide association studies, a relatively new approach to gene discovery.

Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study.

Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population and a larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.

A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin

This study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.

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

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.

Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies

The association between common variants near NOS1AP and the phospholamban gene and PLN, a key regulator of cardiac diastolic function and involved in regulating intracellular calcium cycling, and the QT interval are confirmed.



Common Variants in Myocardial Ion Channel Genes Modify the QT Interval in the General Population: Results From the KORA Study

Previous heritability studies indicating that repolarization is a complex trait with a significant heritable component are confirmed and high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small are demonstrated.

Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia

Y1102 may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications.

Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes

DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.

Genetics of Cardiac Arrhythmias and Sudden Cardiac Death

The current knowledge concerning the molecular basis of cardiac arrhythmias will be summarized and the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways is reviewed.

QT interval is linked to 2 long-QT syndrome loci in normal subjects.

It is suggested that these quantitative trait loci may represent the presence of variations in LQT genes that could be important to the risk for rhythm disturbances in the general population.

QT Interval Prolongation Predicts Cardiovascular Mortality in an Apparently Healthy Population

The results suggest that QT, contributes independently to cardiovascular risk, and it might be speculated that changes in life-style (e.g., with regard to physical exercise and smoking) may have a preventive impact.

Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study.

These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization.

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

It is shown that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do.