Cardiac sodium channel gene variants and sudden cardiac death in women.
BACKGROUND
Several cardiac ion channel genes have been implicated in monogenic traits with a high risk of sudden cardiac death (SCD). Mutations or rare variants in these genes have been proposed as potential contributors to more common forms of SCD, but this hypothesis has not been assessed systematically.


RESULTS
We directly sequenced the entire coding region and splice junctions of 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 SCD cases from 2 large prospective cohorts of women (Nurses' Health Study) and men (Health Professional Follow-Up Study). Controls from the same population were then screened for the presence of mutations or rare variants identified in cases, and sequence variants without prior functional data were expressed in Xenopus oocytes to assess their biophysical consequences. No mutations or rare variants were identified in any of the 53 subjects who were men. In contrast, in 6 of 60 women (10%), we identified 5 rare missense variants in SCN5A that either had been associated previously with long-QT syndrome (A572D and G615E), had been reported to alter sodium channel function (F2004L), or had not been reported previously in control populations (A572F and W1205C). Of the 4 variants without prior functional data, 3 variants were located in the I-II linker (A572D, A572F, and G615E), and all resulted in significantly shorter recovery times from inactivation. When compared with 733 control samples from the same population, the overall frequency of these rare variants in SCN5A was significantly higher in the SCD cases (6/60, 10.0%) than in controls (12/733, 1.6%; P=0.001).


CONCLUSIONS
Functionally significant mutations and rare variants in SCN5A may contribute to SCD risk among women.
Albert
Christine M
CM
Center for Arrhythmia Prevention, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215-1204, USA. calbert@partners.org
Nam
Edwin G
EG
Rimm
Eric B
EB
Jin
Hong Wei
HW
Hajjar
Roger J
RJ
Hunter
David J
DJ
MacRae
Calum A
CA
Ellinor
Patrick T
PT
D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D015222:Sodium Channels / Q000235:genetics*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels