Genetic variation in SCN10A influences cardiac conduction.
To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 x 10(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10(-5) to 10(-20)). SCN10A encodes Na(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.
Chambers
John C
JC
Department of Epidemiology and Public Health, Imperial College London, UK. john.chambers@ic.ac.uk
Zhao
Jing
J
Terracciano
Cesare M N
CM
Bezzina
Connie R
CR
Zhang
Weihua
W
Kaba
Riyaz
R
Navaratnarajah
Manoraj
M
Lotlikar
Amol
A
Sehmi
Joban S
JS
Kooner
Manraj K
MK
Deng
Guohong
G
Siedlecka
Urszula
U
Parasramka
Saurabh
S
El-Hamamsy
Ismail
I
Wass
Mark N
MN
Dekker
Lukas R C
LR
de Jong
Jonas S S G
JS
Sternberg
Michael J E
MJ
McKenna
William
W
Severs
Nicholas J
NJ
de Silva
Ranil
R
Wilde
Arthur A M
AA
Anand
Praveen
P
Yacoub
Magdi
M
Scott
James
J
Elliott
Paul
P
Wood
John N
JN
Kooner
Jaspal S
JS
D000328:Adult; D000368:Aged; D000818:Animals; D044466:Asian People / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D004562:Electrocardiography; D005060:Europe; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006327:Heart Block / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D007194:India; D008297:Male; D051379:Mice; D008875:Middle Aged; D062559:NAV1.8 Voltage-Gated Sodium Channel; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics*; D013686:Telemetry; D014693:Ventricular Fibrillation / Q000150:complications / Q000235:genetics / Q000503:physiopathology
D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels