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

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  • 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
  • Michael W T Tanck
  • Rafik Tadros
  • Arthur A M Wilde
  • Connie R Bezzina
  • Gumpanart Veerakul
  • Koonlawee Nademanee

BACKGROUND: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variation may underlie BrS in a complex inheritance model.

OBJECTIVE: To find common and rare/low frequency genetic variants predisposing to BrS 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=3x10-10). The conditional analysis identified a novel independent signal in the same locus (rs6767797; OR2.3, P=2.7x10-10). The second locus was near HEY2 (lead marker rs3734634; OR2.5, P=7x10-9). Rare (MAF<0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases versus 2.0% in controls, P=0.046, OR=3.3 [1.0-11.1]), but an enrichment of low frequency (MAF<0.001 and >0.0001) variants was also observed in cases, with one variant (SCN5A:p.Arg965Cys), detected in 4.6% of Thai BrS patients vs 0.5% in controls (P=0.015, OR=9.8[1.2-82.3]).

CONCLUSIONS: 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 trans-ethnic transferability of these two major BrS loci.

OriginalsprogEngelsk
TidsskriftHeart Rhythm
ISSN1547-5271
DOI
StatusE-pub ahead of print - 30 jun. 2020

Bibliografisk note

Copyright © 2020. Published by Elsevier Inc.

ID: 244528158