gms | German Medical Science

33rd International Congress on Electrocardiology

International Society of Electrocardiology

Article

Send article

CAPON is a Novel QT-Interval Modifier Gene with Gender Dependent Effect Identified through Genomewide Association Analysis in Individuals from the General Population

Meeting Abstract

Search Medline for

  • corresponding author presenting/speaker A. Pfeufer - Institut of Human Genetics Technical Univ., München, Germany
  • D.E. Arking - John Hopkins Medical Institutes, Baltimore, USA
  • S. Perz - GSF National research Center, Neuherberg, Germany
  • M. Akyol - GSF National research Center, Neuherberg, Germany
  • S. Jalilzadeh - Institut of Human Genetics Technical Univ., München, Germany
  • W. Post - John Hopkins Medical Institutes, Baltimore, USA
  • T. Illig - GSF National research Center, Neuherberg, Germany
  • C. Gieger - GSF National research Center, Neuherberg, Germany
  • H.E. Wichmann - GSF National research Center, Neuherberg, Germany
  • E. Marban - John Hopkins Medical Institutes, Baltimore, USA
  • P.M. Spooner - John Hopkins Medical Institutes, Baltimore, USA
  • A. Chakravarti - John Hopkins Medical Institutes, Baltimore, USA
  • T. Meitinger - nstitut of Human Genetics Technical Univ., München, Germany
  • S. Kaab - Dept. of Medicine, University Munich, München, Germany

33rd International Congress on Electrocardiology. Cologne, 28.06.-01.07.2006. Düsseldorf, Köln: German Medical Science; 2007. Doc06ice014

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/ice2006/06ice014.shtml

Published: February 8, 2007

© 2007 Pfeufer et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

Text

Background: The QT interval is a normally distributed trait in the general population and reflects cardiac repolarization. It has a heritability between 30% and 50% and - if shortened, prolonged or otherwise unregular - predisposes individuals to sudden cardiac death. Some of the QT modifier genes identified today display profound gender dependent effects.

Aim: To map novel modifier genes for QT interval we performed a genome-wide SNP association study using 100k arrays.

Method: From the population-based KORA S4 survey (n=3,966 after exclusion criteria, including n=2,007 women) 100/100 women - to avoid gender confounding - were selected from the extremes of the corrected QT distribution (below 7.5th and above 92.5th percentile) and were genotyped for 88.500 SNPs with call rate >0.85 and minor allele frequency >0.025 (phase I). 60 SNPs were genotyped in an additional 200/200 women (phase II). 7 SNPs significant at (p<5*10-3) in combined phase I and II where screened in the remaining n=3,366 of S4 (phase III).

Results: Only one SNP in the 5’ region of the CAPON/NOS1AP gene clearly exceeded the genomewide significance level (p<10-7). We successfully replicated the association between CAPON and the QT-interval in n=2,646 independent individuals from the KORA F3 study (p<10-11). The effect was stronger in women than in men.

Conclusions: We identified the CAPON (NOS1AP) gene as a novel modifier of QT influencing it by about +6 ms and explaining some 1.5% of trait variance. Its effect is thus much stronger than those of the previously identified KCNH2-K897T or KCNQ1-Intron1 variants. Studies of CAPON effect size across European populations and a similar genome-wide study employing 100/100 men are currently underway as is its functional characterization. The genome-wide association analysis of ECG signatures in general population samples provides an innovative and efficient route to identify novel genes involved in cardiac electrophysiology avoiding the necessity to recruit affected patients.