Pattarapong Makarawate1, Charlotte Glinge2, Apichai Khongphatthanayothin3, Roddy Walsh4, John Mauleekoonphairoj5, Montawatt Amnueypol6, Somchai Prechawat7, Wanwarang Wongcharoen8, Rungroj Krittayaphong9, Alisara Anannab10, Peter Lichtner11, Thomas Meitinger11, Fleur V Y Tjong4, Krystien V V Lieve4, Ahmad S Amin4, Dujdao Sahasatas1, Tachapong Ngarmukos6, Duangdao Wichadakul12, Sunchai Payungporn13, Boosamas Sutjaporn5, Pharawee Wandee5, Yong Poovorawan5, Jacob Tfelt-Hansen14, Michael W T Tanck15, Rafik Tadros16, Arthur A M Wilde17, Connie R Bezzina17, Gumpanart Veerakul18, Koonlawee Nademanee19. 1. Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 2. Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 3. Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Bangkok Heart Hospital, Bangkok General Hospital, Bangkok, Thailand. Electronic address: apichaik@yahoo.com. 4. Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. 5. Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 6. Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 7. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 8. Department of Medicine, Faculty of Medicine, Chiangmai University, Chiangmai, Thailand. 9. Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. 10. Department of cardiovascular and intervention, Central Chest Institute of Thailand, Nonthaburi, Thailand. 11. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 12. Department of Computer Engineering, Faculty of Engineering, Chulalongkorn University, Bangkok, Thailand. 13. Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 14. The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu). 15. Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health, Amsterdam, The Netherlands. 16. Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada. 17. Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu). 18. Bangkok Heart Hospital, Bangkok General Hospital, Bangkok, Thailand. 19. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Pacific Rim Electrophysiology Research Institute, Bumrungrad Hospital, Bangkok, Thailand.
Abstract
BACKGROUND: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model. OBJECTIVE: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand. METHODS: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants. RESULTS: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3). CONCLUSION: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.
BACKGROUND: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model. OBJECTIVE: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand. METHODS: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants. RESULTS: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3). CONCLUSION: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.
Authors: Yan Huang; Xiao-Meng Chen; Hector Barajas-Martinez; Hong Jiang; Charles Antzelevitch; Dan Hu Journal: Hum Mol Genet Date: 2021-12-27 Impact factor: 5.121