Genetic association of common variants with a rare cardiac disease, the Brugada Syndrome, in a multi-centric study. C. Dina1,2, J. Barc3, Y. Mizusawa3, C. A. Remme3, J. B. Gourraud1,2, F. Simonet1, P. J. Schwartz4, L. Crotti4, P. Guicheney5, A. Leenhardt6, C. Antzelevitch7, E. Schulze-Bahr8, E. R. Behr9, J. Tfelt-Hansen10, S. Kaab11, H. Watanabe12, M. Horie13, N. Makita14, W. Shimizu15, P. Froguel16, B. Balkau17, M. Gessler18, D. Roden19, V. M. Christoffels3, H. Le Marec1,2, A. A. Wilde3, V. Probst1,2, J. J. Schott1,2, R. Redon1,2, C. R. Bezzina3 1) Thorx Inst, INSERM UMR 1087, CNRS, Nantes, France; 2) CHU Nantes, l'institut du thorax, Nantes, France; 3) Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands; 4) University of Pavia, Pavia, Italy,; 5) Inserm UMR 956, UPMC, Paris, France,; 6) Cardiology Unit, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Nantes, France,; 7) Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, United States,; 8) Department of Cardiovascular Medicine, University Hospital, Münster, Germany,; 9) Cardiovascular Sciences Research Centre, St George's University, London, United Kingdom,; 10) Laboratory of Molecular Cardiology, University of Copenhagen, Copenhagen, Denmark,; 11) 1Department of Medicine I, Ludwig-Maximilians University, Munich, Germany,; 12) Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan,; 13) Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan,; 14) Department of Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan,; 15) Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan,; 16) CNRS UMR 8199, Pasteur Institute, Lille, France,; 17) Inserm UMR 1018, Centre for research in Epidemiology and Population Health, Villejuif, France,; 18) Theodor-Boveri-Institute, University of Wuerzburg, Wuerzburg, Germany,; 19) Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States.

   The Brugada Syndrome (BrS) is considered as a rare Mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific electrocardiographic features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A, encoding the pore-forming subunit of the cardiac sodium channel (Nav1.5), are identified in ~20% of patients. However, studies in families harbouring mutations in SCN5A have demonstrated low disease penetrance and in some instances absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Two genomic regions displayed significant association. Both associations were replicated on two independent case/control sets from Europe (598/855) and Japan (208/1016) and a third locus emerged, all three with extremely significant p-values (1.10-14 down to 1.10-68). To our knowledge, this is the first time that several common variants are associated with a rare disease, with very high effect (Osdds-ratio) ranging from 1.58 to 2.55. While two loci displaying association hits had already been shown to influence ECG parameters in the general population, the third one encompasses a transcription factor which had never been related to cardiac arrhythmia. We showed that this factor regulates Nav1.5 channel expression in hearts of homozygous knockout embryos and influence cardiac conduction velocity in adult heterozygous mice. At last, we found that the cumulative effect of the 3 loci on disease susceptibility was unexpectedly large, indicating that common genetic variation may have a strong impact on predisposition to rare disease.

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