Published in
Elsevier, Gastroenterology, 7(146), p. 1659-1668, 2014
DOI: 10.1053/j.gastro.2014.02.054
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Loss-of-function of the Voltage-gated Sodium Channel NaV1.5 (Channelopathies) in Patients with Irritable Bowel Syndrome
,
Strege Pr,
Peter R. Strege,
David J. Tester,
Tester Dj,
Yuri A. Saito,
Cheryl E. Bernard,
Bernard Ce,
Felicity T. Enders,
Weronica E. Ek,
Enders Ft,
Peter T. Schmidt
and other authors.
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Abstract
Background & Aims: SCN5A encodes the α-subunit of the voltage-gated sodium channel Na V 1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na V 1.5. Methods: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P