PuSH - Publikationsserver des Helmholtz Zentrums München

Kolder, I.C.* ; Tanck, M.W.* ; Postema, P.G.* ; Barc, J.* ; Sinner, M.F.* ; Zumhagen, S.* ; Husemann, A.* ; Stallmeyer, B.* ; Koopmann, T.T.* ; Hofman, N.* ; Pfeufer, A. ; Lichtner, P. ; Meitinger, T. ; Beckmann, B.M.* ; Myerburg, R.J.* ; Bishopric, N.H.* ; Roden, D.M.* ; Kääb, S.* ; Wilde, A.A.* ; Schott, J.J.* ; Schulze-Bahr, E.* ; Bezzina, C.R.*

Analysis for genetic modifiers of disease severity in patients with long QT syndrome type 2.

Circ. Cardiovasc. Genet. 8, 447-456 (2015)
Postprint Anhang DOI PMC
Open Access Green
BACKGROUND: -Considerable interest exists in the identification of genetic modifiers of disease severity in the Long QT Syndrome (LQTS) as their identification may contribute to refinement of risk stratification. METHODS AND RESULTS: -We searched for single nucleotide polymorphisms (SNPs) that modulate the QTc-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1,201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies (GWAS) in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, p=9.5×10(-8); rs12143842, p=4.8×10(-7); rs2880058, p=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454, OR=1.85 [95% CI, 1.32-2.59], p=3×10(-4)) and KCNQ1 (rs12576239; OR=1.84 [95% CI, 1.31-2.60], p=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multi-locus genetic risk score (GRSNOS1AP) uncovered a strong linear relationship between GRSNOS1AP and the QTc-interval (p=4.2×10(-7)). Furthermore, patients with a GRSNOS1AP in the lowest quartile had a lower relative risk of cardiac events compared to patients in the other quartiles combined (p=0.039). CONCLUSIONS: -We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time we linked common genetic variation at KCNQ1 with risk for LQTS.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Arrhythmia ; Association Study ; Genetic Risk Score ; Ion Channel ; Long Qt Syndrome ; Polymorphism Genetics; Modulates Cardiac Repolarization; Interval Duration; Common Variants; Risk; Association; Impact; Heart
ISSN (print) / ISBN 1942-325X
e-ISSN 1942-3268
Zeitschrift Circulation: Cardiovascular Genetics
Quellenangaben Band: 8, Heft: 3, Seiten: 447-456 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Hagerstown, Md
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Human Genetics (IHG)