title: Genetic variation in SCN10A influences cardiac conduction.
abstract: 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.
authors.affiliation: Department of Epidemiology and Public Health, Imperial College London, UK. john.chambers@ic.ac.uk
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Cesare M N
authors.initials: CM
authors.lastname: Terracciano
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.forename: Riyaz
authors.initials: R
authors.lastname: Kaba
authors.forename: Manoraj
authors.initials: M
authors.lastname: Navaratnarajah
authors.forename: Amol
authors.initials: A
authors.lastname: Lotlikar
authors.forename: Joban S
authors.initials: JS
authors.lastname: Sehmi
authors.forename: Manraj K
authors.initials: MK
authors.lastname: Kooner
authors.forename: Guohong
authors.initials: G
authors.lastname: Deng
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.forename: Saurabh
authors.initials: S
authors.lastname: Parasramka
authors.forename: Ismail
authors.initials: I
authors.lastname: El-Hamamsy
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wass
authors.forename: Lukas R C
authors.initials: LR
authors.lastname: Dekker
authors.forename: Jonas S S G
authors.initials: JS
authors.lastname: de Jong
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
authors.forename: William
authors.initials: W
authors.lastname: McKenna
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Severs
authors.forename: Ranil
authors.initials: R
authors.lastname: de Silva
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
authors.forename: Magdi
authors.initials: M
authors.lastname: Yacoub
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
mesh_terms: 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
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels