Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
Nolte
Ilja M
IM
Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Wallace
Chris
C
Newhouse
Stephen J
SJ
Waggott
Daryl
D
Fu
Jingyuan
J
Soranzo
Nicole
N
Gwilliam
Rhian
R
Deloukas
Panos
P
Savelieva
Irina
I
Zheng
Dongling
D
Dalageorgou
Chrysoula
C
Farrall
Martin
M
Samani
Nilesh J
NJ
Connell
John
J
Brown
Morris
M
Dominiczak
Anna
A
Lathrop
Mark
M
Zeggini
Eleftheria
E
Wain
Louise V
LV
Newton-Cheh
Christopher
C
Eijgelsheim
Mark
M
Rice
Kenneth
K
de Bakker
Paul I W
PI
Pfeufer
Arne
A
Sanna
Serena
S
Arking
Dan E
DE
Asselbergs
Folkert W
FW
Spector
Tim D
TD
Carter
Nicholas D
ND
Jeffery
Steve
S
Tobin
Martin
M
Caulfield
Mark
M
Snieder
Harold
H
Paterson
Andrew D
AD
Munroe
Patricia B
PB
Jamshidi
Yalda
Y
D002135:Calcium-Binding Proteins / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006321:Heart / Q000502:physiology*; D006801:Humans; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000099211:Phospholamban