Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

Pattarapong Makarawate; Charlotte Glinge; Apichai Khongphatthanayothin; Roddy Walsh; John Mauleekoonphairoj; Montawatt Amnueypol; Somchai Prechawat; Wanwarang Wongcharoen; Rungroj Krittayaphong; Alisara Anannab; Peter Lichtner; Thomas Meitinger; Fleur V Y Tjong; Krystien V V Lieve; Ahmad S Amin; Dujdao Sahasatas; Tachapong Ngarmukos; Duangdao Wichadakul; Sanchai Payungporn; Boosamas Sutjaporn; Pharawee Wandee; Yong Poovorawan; Jacob Tfelt-Hansen; Michael W T Tanck; Rafik Tadros; Arthur A M Wilde; Connie R Bezzina; Gumpanart Veerakul; Koonlawee Nademanee

doi:https://doi.org/10.1016/j.hrthm.2020.06.027

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

Pattarapong Makarawate, Charlotte Glinge, Apichai Khongphatthanayothin, Roddy Walsh, John Mauleekoonphairoj, Montawatt Amnueypol, Somchai Prechawat, Wanwarang Wongcharoen, Rungroj Krittayaphong, Alisara Anannab, Peter Lichtner, Thomas Meitinger, Fleur V Y Tjong, Krystien V V Lieve, Ahmad S Amin, Dujdao Sahasatas, Tachapong Ngarmukos, Duangdao Wichadakul, Sanchai Payungporn, Boosamas SutjapornPharawee Wandee, Yong Poovorawan, Jacob Tfelt-Hansen, Michael W T Tanck, Rafik Tadros, Arthur A M Wilde, Connie R Bezzina, Gumpanart Veerakul, Koonlawee Nademanee

Research output: Contribution to journal › Article › Academic › peer-review

24 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2145-2153
Number of pages	9
Journal	Heart Rhythm
Volume	17
Issue number	12
Early online date	30 Jun 2020
DOIs	https://doi.org/10.1016/j.hrthm.2020.06.027
Publication status	Published - Dec 2020

Keywords

Brugada syndrome
Genetics
Genome-wide association study
SCN5A
Thailand

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Makarawate, P., Glinge, C., Khongphatthanayothin, A., Walsh, R., Mauleekoonphairoj, J., Amnueypol, M., Prechawat, S., Wongcharoen, W., Krittayaphong, R., Anannab, A., Lichtner, P., Meitinger, T., Tjong, F. V. Y., Lieve, K. V. V., Amin, A. S., Sahasatas, D., Ngarmukos, T., Wichadakul, D., Payungporn, S., ... Nademanee, K. (2020). Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand. Heart Rhythm, 17(12), 2145-2153. https://doi.org/10.1016/j.hrthm.2020.06.027

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title = "Common and rare susceptibility genetic variants predisposing to Brugada syndrome in 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.",

keywords = "Brugada syndrome, Genetics, Genome-wide association study, SCN5A, Thailand",

author = "Pattarapong Makarawate and Charlotte Glinge and Apichai Khongphatthanayothin and Roddy Walsh and John Mauleekoonphairoj and Montawatt Amnueypol and Somchai Prechawat and Wanwarang Wongcharoen and Rungroj Krittayaphong and Alisara Anannab and Peter Lichtner and Thomas Meitinger and Tjong, {Fleur V Y} and Lieve, {Krystien V V} and Amin, {Ahmad S} and Dujdao Sahasatas and Tachapong Ngarmukos and Duangdao Wichadakul and Sanchai Payungporn and Boosamas Sutjaporn and Pharawee Wandee and Yong Poovorawan and Jacob Tfelt-Hansen and Tanck, {Michael W T} and Rafik Tadros and Wilde, {Arthur A M} and Bezzina, {Connie R} and Gumpanart Veerakul and Koonlawee Nademanee",

year = "2020",

month = dec,

doi = "https://doi.org/10.1016/j.hrthm.2020.06.027",

language = "English",

volume = "17",

pages = "2145--2153",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier",

number = "12",

}

Makarawate, P, Glinge, C, Khongphatthanayothin, A, Walsh, R, Mauleekoonphairoj, J, Amnueypol, M, Prechawat, S, Wongcharoen, W, Krittayaphong, R, Anannab, A, Lichtner, P, Meitinger, T, Tjong, FVY , Lieve, KVV, Amin, AS, Sahasatas, D, Ngarmukos, T, Wichadakul, D, Payungporn, S, Sutjaporn, B, Wandee, P, Poovorawan, Y, Tfelt-Hansen, J, Tanck, MWT, Tadros, R, Wilde, AAM , Bezzina, CR, Veerakul, G & Nademanee, K 2020, 'Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand', Heart Rhythm, vol. 17, no. 12, pp. 2145-2153. https://doi.org/10.1016/j.hrthm.2020.06.027

TY - JOUR

T1 - Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

AU - Makarawate, Pattarapong

AU - Glinge, Charlotte

AU - Khongphatthanayothin, Apichai

AU - Walsh, Roddy

AU - Mauleekoonphairoj, John

AU - Amnueypol, Montawatt

AU - Prechawat, Somchai

AU - Wongcharoen, Wanwarang

AU - Krittayaphong, Rungroj

AU - Anannab, Alisara

AU - Lichtner, Peter

AU - Meitinger, Thomas

AU - Tjong, Fleur V Y

AU - Lieve, Krystien V V

AU - Amin, Ahmad S

AU - Sahasatas, Dujdao

AU - Ngarmukos, Tachapong

AU - Wichadakul, Duangdao

AU - Payungporn, Sanchai

AU - Sutjaporn, Boosamas

AU - Wandee, Pharawee

AU - Poovorawan, Yong

AU - Tfelt-Hansen, Jacob

AU - Tanck, Michael W T

AU - Tadros, Rafik

AU - Wilde, Arthur A M

AU - Bezzina, Connie R

AU - Veerakul, Gumpanart

AU - Nademanee, Koonlawee

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

KW - Brugada syndrome

KW - Genetics

KW - Genome-wide association study

KW - SCN5A

KW - Thailand

UR - http://www.scopus.com/inward/record.url?scp=85091722293&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.hrthm.2020.06.027

DO - https://doi.org/10.1016/j.hrthm.2020.06.027

M3 - Article

C2 - 32619740

SN - 1547-5271

VL - 17

SP - 2145

EP - 2153

JO - Heart Rhythm

JF - Heart Rhythm

IS - 12

ER -

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

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Keywords

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