Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

被引：391

作者：

Bezzina, Connie R. ^{[1
]}

Barc, Julien ^{[1
,2
]}

Mizusawa, Yuka ^{[1
]}

Remme, Carol Ann ^{[1
]}

Gourraud, Jean-Baptiste ^{[3
,4
,5
,6
]}

Simonet, Floriane ^{[3
,4
,5
]}

Verkerk, Arie O. ^{[7
]}

Schwartz, Peter J. ^{[8
,9
,10
,11
,12
,13
]}

Crotti, Lia ^{[8
,9
,14
]}

Dagradi, Federica ^{[8
,9
]}

Guicheney, Pascale ^{[15
,16
]}

Fressart, Veronique ^{[15
,16
,17
]}

Leenhardt, Antoine ^{[18
,19
,20
]}

Antzelevitch, Charles ^{[21
]}

Bartkowiak, Susan ^{[21
]}

Schulze-Bahr, Eric ^{[22
]}

Zumhagen, Sven ^{[22
]}

Behr, Elijah R. ^{[23
]}

Bastiaenen, Rachel ^{[23
]}

Tfelt-Hansen, Jacob ^{[24
,25
]}

Olesen, Morten Salling ^{[24
,25
]}

Kaeaeb, Stefan ^{[26
,27
]}

Beckmann, Britt M. ^{[26
]}

Weeke, Peter ^{[28
]}

Watanabe, Hiroshi ^{[29
]}

Endo, Naoto ^{[30
]}

Minamino, Tohru ^{[29
]}

Horie, Minoru ^{[31
]}

Ohno, Seiko ^{[31
]}

Hasegawa, Kanae ^{[31
]}

Makita, Naomasa ^{[32
]}

Nogami, Akihiko ^{[33
]}

Shimizu, Wataru ^{[34
,35
]}

Aiba, Takeshi ^{[35
]}

Froguel, Philippe ^{[36
,37
,38
]}

Balkau, Beverley ^{[39
,40
]}

Lantieri, Olivier ^{[41
]}

Torchio, Margherita ^{[8
,9
]}

Wiese, Cornelia ^{[42
]}

Weber, David ^{[42
]}

Wolswinkel, Rianne ^{[1
]}

Coronel, Ruben ^{[1
]}

Boukens, Bas J. ^{[1
,7
]}

Bezieau, Stephane ^{[43
]}

Charpentier, Eric ^{[3
,4
,5
]}

Chatel, Stephanie ^{[3
,4
,5
,6
]}

Despres, Aurore ^{[3
,4
,5
,6
]}

Gros, Francoise ^{[3
,4
,5
]}

Kyndt, Florence ^{[3
,4
,5
,6
,43
]}

Lecointe, Simon ^{[3
,4
,5
,6
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Dept Clin & Expt Cardiol, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[2] ICIN Netherlands Heart Inst, Utrecht, Netherlands

[3] INSERM, UMR 1087, Inst Thorax, Nantes, France

[4] CNRS, UMR 6291, Nantes, France

[5] Univ Nantes, Nantes, France

[6] Ctr Hosp Univ CHU Nantes, Inst Thorax, Serv Cardiol, Nantes, France

[7] Univ Amsterdam, Acad Med Ctr, Dept Anat Embryol & Physiol, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[8] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy

[9] Ist Auxol Italiano, IRCCS, Ctr Cardiac Arrhythmias Genet Origin, Milan, Italy

[10] Hatter Inst Cardiovasc Res Africa, Cardiovasc Genet Lab, Cape Town, South Africa

[11] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa

[12] Univ Stellenbosch, Dept Med, ZA-7600 Stellenbosch, South Africa

[13] King Saud Univ, Coll Med, Dept Family & Community Med, Chair Sudden Death, Riyadh 11461, Saudi Arabia

[14] Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany

[15] Fac Med Pierre & Marie Curie, INSERM, U956, Paris, France

[16] Univ Paris 06, Inst Federatif Rech 14, UMRS 956, Paris, France

[17] Grp Hosp Pitie Salpetriere, AP HP, Serv Biochim Metab, Unite Fonct Cardiogenet & Myogenet Mol & Cellulai, F-75634 Paris, France

[18] Hop Bichat Claude Bernard, AP HP, Serv Cardiol, Ctr Reference Malad Cardiaques Hereditaires, F-75877 Paris, France

[19] INSERM, U698, Paris, France

[20] Univ Paris Diderot, Paris, France

[21] Masonic Med Res Lab, Dept Expt Cardiol, Utica, NY USA

[22] Univ Hosp, Inst Genet Heart Dis IfGH, Dept Cardiovasc Med, Munster, Germany

[23] St Georges Univ London, Cardiovasc Sci Res Ctr, London, England

[24] Univ Copenhagen, Mol Cardiol Lab, Danish Natl Res Fdn Ctr Cardiac Arrhythmia DARC, Copenhagen, Denmark

[25] Rigshosp, Copenhagen Univ Hosp, Dept Cardiol, Ctr Heart, DK-2100 Copenhagen, Denmark

[26] Univ Munich, Univ Hosp Munich, Dept Med 1, Munich, Germany

[27] Deutsch Forschungszentrum Herz Kreislauferkrankun, Partner Site Munich Heart Alliance, Munich, Germany

[28] Vanderbilt Univ, Sch Med, Dept Med & Pharmacol, Nashville, TN 37212 USA

[29] Niigata Univ, Grad Sch Med & Dent Sci, Dept Cardiovasc Biol & Med, Niigata, Japan

[30] Niigata Univ, Grad Sch Med & Dent Sci, Dept Regenerat & Transplant Med, Div Orthopaed Surg, Niigata, Japan

[31] Shiga Univ Med Sci, Dept Cardiovasc & Resp Med, Otsu, Shiga 52021, Japan

[32] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Physiol, Nagasaki 852, Japan

[33] Yokohama Rosai Hosp, Div Heart Rhythm Management, Yokohama, Kanagawa, Japan

[34] Nippon Med Sch, Dept Cardiovasc Med, Tokyo 113, Japan

[35] Natl Cerebral & Cardiovasc Ctr, Dept Cardiovasc Med, Div Arrhythmia & Electrophysiol, Suita, Osaka, Japan

[36] Lille Pasteur Inst, CNRS, UMR 8199, Lille, France

[37] Lille Nord France Univ, Lille, France

[38] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London, England

[39] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France

[40] Univ Paris 11, UMRS 1018, Villejuif, France

[41] Inst Inter Reg Sante IRSA, La Riche, France

[42] Univ Wurzburg, Theodor Boveri Inst, Bioctr, D-97070 Wurzburg, Germany

[43] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France

来源：

NATURE GENETICS | 2013年 / 45卷 / 09期

关键词：

GENOME-WIDE ASSOCIATION; QT INTERVAL DURATION; ST-SEGMENT ELEVATION; BUNDLE-BRANCH BLOCK; GENETIC-VARIATION; CONDUCTION SYSTEM; LOCI; EXPRESSION; HETEROGENEITY; SCN10A;

D O I：

10.1038/ng.2712

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases(1-3). Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 x 10(-68); rs9388451, P = 5.1 x 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 x 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (P-trend = 6.1 x 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction(4-7) can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development(8). Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

引用

页码：1044 / +

页数：9

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