Qt Interval, Variation In

Description

The electrocardiographic (ECG) QT interval, a measure of cardiac repolarization, is a genetically influenced quantitative trait with estimated heritability of approximately 30% (Arking et al., 2006). Very long or short QT intervals occur in a heterogeneous collection of mendelian disorders, the various forms of long QT syndrome (LQTS; see 192500) and short QT syndrome (SQTS; see 609620). These are usually due to rare, highly penetrant mutations in ion channel genes that are associated with increased risk of sudden cardiac death (SCD; see 115080). Familial clustering of SCD has been observed, but the vast majority of subjects who are at risk for SCD do not have mutations in the known genes for LQTS or SQTS.

Mapping

To identify genetic mechanisms by which an altered QT interval may contribute to SCD risk, Arking et al. (2006) examined the QT interval directly as opposed to the SCD phenotype, treating the QT interval as a quantitative trait that could be accurately and reliably measured in large samples from standard ECG recordings. In a genomewide study involving 200 individuals at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, the authors found an association between QT interval and common genetic variants in noncoding regions of the NOS1 regulator NOS1AP (605551) on chromosome 1q23.3.

Post et al. (2007) replicated the association between variants in the NOS1AP gene and QT interval (p = 0.006) in a genetically homogeneous population of Old Order Amish.

In a population-based prospective cohort of 5,374 Dutch individuals aged 55 years and older, Aarnoudse et al. (2007) determined the heart rate-corrected QT interval (QTc) and genotyped 2 SNPs in the NOS1AP gene. The authors found that the G allele of rs10494366 (36% frequency) was associated with a 3.8-ms increase in QTc for each additional allele copy (p = 7.8 x 10(-20)); and the G allele of rs10918594 (31% frequency) was associated with a 3.6-ms increase in QTc per allele copy (p = 6.9 x 10 (-17)). Over an 11.9-year follow-up period, there were 233 sudden cardiac deaths; no significant association was observed with sudden cardiac death. Aarnoudse et al. (2007) stated that the 2 SNPs, which are 55 kb apart, are not known to be functional and are not highly correlated with any known functional SNP. They suggested the existence of a causal untyped SNP that is correlated with both SNPs.

Eijgelsheim et al. (2009) performed fine mapping of the association of the NOS1AP locus with QT interval within the Rotterdam Study, a population-based, prospective cohort study of individuals 55 years of age or older. The authors tested the association of SNPs in or within 100 kb of the NOS1AP gene with QT interval duration, using the combined set of SNPs present in the Affymetrix 500k and Illumina 550k chip arrays. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T allele frequency = 24%) was associated with a QT interval duration increase of 4.4 ms per additional T allele (P = 4.4 x 10(-28)). For comparison, the most strongly associated variant to that time, rs10494366, was associated with a 3.5-ms increase (P = 1.6 x 10(-23)) per additional G allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842 SNP.

Marroni et al. (2009) performed genomewide association scanning of 3 European genetically isolated populations from Italy, Scotland, and the Netherlands and confirmed an association between QT interval and the NOS1AP gene (rs10494366; p = 8.72 x 10(-8)). The strongest association signal was for a SNP rs2880058 located 25 kb upstream of NOS1AP (p = 2.0 x 10(-10)). They also identified a SNP rs2478333 on chromosome 13 located 100 kb from LOC730174 and 300 kb from the SUCLA2 gene (603921).

Associations Pending Confirmation

Kim et al. (2012) performed a genomewide association study of 6,805 Asian individuals (Korean, Japanese, and Chinese) and found significant association between a SNP (rs13017846) near the SLC8A1 gene (182305) and shorter QT intervals (p = 8.0 x 10(-14)).

Using a genomewide association and replication study in up to 100,000 individuals, Arking et al. (2014) identified 35 common variant loci associated with QT interval that collectively explain approximately 8 to 10% of QT interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins.