rs10494366 (NOS1AP): QT Interval and Cardiac Repolarization
Key takeaways
- rs10494366 in NOS1AP was among the first genome-wide significant variants linked to cardiac repolarization (QT interval).
- About 60% of people of European ancestry carry at least one copy of the minor allele.
- The variant explains up to 1.5% of QT interval variation across European-ancestry cohorts.
- QT interval extremes are associated with increased cardiovascular mortality.
- GTEx data show this variant reduces NOS1AP expression in the heart and brain, and increases it in subcutaneous fat tissue.
Key takeaways
- rs10494366 is a common variant in NOS1AP (also known as CAPON), a gene encoding a regulator of neuronal nitric oxide synthase, and was among the first genome-wide significant variants linked to cardiac repolarization (the QT interval).
- About 60% of people of European ancestry carry at least one copy of the minor allele.
- The variant explains up to 1.5% of QT interval variation in European-ancestry cohorts.
- QT interval extremes are associated with increased cardiovascular mortality, making this locus of interest to cardiac researchers.
- GTEx tissue data show this variant is linked to reduced NOS1AP and C1orf226 expression in the heart and increased NOS1AP expression in subcutaneous fat tissue.
What the research says A 2006 genome-wide association study (GWAS) of cardiac repolarization, measured as the QT interval on an electrocardiogram (a recording of the heart's electrical activity), identified a common variant in NOS1AP (also called CAPON, a gene encoding a regulator of neuronal nitric oxide synthase) as a significant modulator of this trait, using an initial sample drawn from 3,966 individuals in the KORA cohort in Germany PMID 16648850. The finding was validated in two independent cohorts totaling approximately 4,451 additional subjects (2,646 from Germany and 1,805 from the US Framingham Heart Study), and approximately 60% of subjects of European ancestry carry at least one minor allele of this locus, explaining up to 1.5% of the interval's variation PMID 16648850.
Reported associations
- QT interval (cardiac repolarization): The rs10494366 variant in NOS1AP modulates QT interval duration, explaining up to 1.5% of variation in European-ancestry cohorts totaling over 8,000 individuals; extremes of this interval are associated with increased cardiovascular mortality PMID 16648850.
Evidence quality The primary evidence comes from a staged GWAS: discovery in 200 subjects at QT interval extremes from a population of 3,966 (KORA cohort, Germany), validated in two independent cohorts (2,646 from Germany; 1,805 from the Framingham Heart Study, US), for a combined sample of approximately 8,400 individuals, all of European ancestry PMID 16648850. The variant explains up to 1.5% of QT interval variation across these samples, and no conflicting findings are reported in the provided studies. A separate 2010 GWAS of approximately 20,000 European-descent individuals focused on heart rate, PR interval, and QRS duration also noted replication of previously described QT interval associations, consistent with the robustness of this trait's genetic architecture PMID 20062063. A multi-ethnic GWAS framework study of 49,839 non-European individuals has demonstrated that effect sizes from European-ancestry GWAS may not generalize to other ancestries PMID 31217584, so the applicability of the NOS1AP finding to non-European populations has not been established in the available literature.
Tissue-specific expression effects
- NOS1AP: The variant is associated with reduced expression of this gene in the brain (cerebellar hemisphere), heart (left ventricle), and esophagus (muscularis layer), and with increased expression in subcutaneous fat tissue GTEx Portal.
- C1orf226: The variant is associated with increased C1orf226 expression in the spleen and reduced C1orf226 expression in the heart (left ventricle and atrial appendage) and esophagus (muscularis layer) GTEx Portal.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does NOS1AP do?
NOS1AP (also called CAPON) encodes a protein that regulates neuronal nitric oxide synthase, an enzyme involved in cellular signaling. Variants in this gene have been linked to the QT interval, the heart's electrical recovery time between beats.
What is the QT interval and why does it matter?
The QT interval is a measurement on an electrocardiogram (ECG) reflecting how long the heart takes to electrically recover after each beat, a process called repolarization. Research shows that extremes of QT interval are associated with increased cardiovascular mortality.
How common is rs10494366?
About 60% of people of European ancestry carry at least one copy of the minor allele at rs10494366. Its frequency and effects in other ancestries have not been established in the available literature.
Is rs10494366 linked to heart disease?
Research shows rs10494366 influences QT interval length, explaining up to 1.5% of its variation. The research notes that extreme QT interval values are associated with cardiovascular mortality, but the available studies do not directly link carrying this variant to a specific disease outcome.
Which tissues does rs10494366 affect gene expression in?
GTEx data show this variant is associated with reduced NOS1AP expression in the heart, brain, and esophagus, and increased expression in subcutaneous fat. It is also associated with reduced expression of a nearby gene, C1orf226, in the heart and esophagus, and increased C1orf226 expression in the spleen.