title: A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.
abstract: Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A(I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A(I334V) (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A(I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A(I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A(I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.
authors.affiliation: Department of Cardiovascular Medicine, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan. nakanoy@hiroshima-u.ac.jp
authors.forename: Yukiko
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authors.lastname: Nakano
authors.forename: Kazuaki
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authors.lastname: Chayama
authors.forename: Hidenori
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authors.lastname: Ochi
authors.forename: Masaaki
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authors.lastname: Toshishige
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authors.forename: C Nelson
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authors.forename: Hidekazu
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authors.lastname: Suzuki
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authors.lastname: Tokuyama
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authors.lastname: Oda
authors.forename: Kazuyoshi
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authors.lastname: Suenari
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authors.lastname: Uchimura-Makita
authors.forename: Kenta
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authors.lastname: Kajihara
authors.forename: Akinori
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authors.lastname: Sairaku
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authors.lastname: Motoda
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authors.lastname: Fujiwara
authors.forename: Yoshikazu
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authors.lastname: Watanabe
authors.forename: Yukihiko
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authors.lastname: Yoshida
authors.forename: Kimie
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authors.lastname: Ohkubo
authors.forename: Ichiro
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authors.lastname: Watanabe
authors.forename: Akihiko
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authors.lastname: Nogami
authors.forename: Kanae
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authors.lastname: Hasegawa
authors.forename: Hiroshi
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authors.lastname: Watanabe
authors.forename: Naoto
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authors.lastname: Endo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006321:Heart / Q000294:innervation / Q000503:physiopathology; D006323:Heart Arrest / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D012307:Risk Factors; D040121:Semaphorin-3A / Q000235:genetics* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: C108639:SEMA3A protein, human; D040121:Semaphorin-3A