Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
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.
Heart Rhythm. 2020 Dec;17(12):2145-2153. doi: 10.1016/j.hrthm.2020.06.027. Epub 2020 Jun 30.
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.
The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.
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.
Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10). 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).
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.
SCN5A 突变在泰国 Brugada 综合征（BrS）患者中很少见。最近的证据表明，常见的遗传变异可能在复杂的遗传模式下导致 BrS。
本研究旨在寻找导致泰国人 BrS 的常见和罕见/低频遗传变异。
我们进行了全基因组关联研究（GWAS），以探讨 154 例泰国 BrS 病例和 432 例对照中常见变异的相关性。我们对 131 例病例和 205 例对照进行了 SCN5A 测序。根据现行指南对变异进行分类，并对罕见和低频变异进行病例对照关联测试。
有两个基因座与 BrS 显著相关。第一个位于 SCN5A/SCN10A 附近（先导标记 rs10428132；优势比 [OR] 2.4；P = 3×10）。条件分析在同一基因座中确定了一个新的独立信号（rs6767797；OR 2.3；P = 2.7×10）。第二个基因座位于 HEY2 附近（先导标记 rs3734634；OR 2.5；P = 7×10）。在 131 例病例中有 8 例发现 SCN5A 罕见（次要等位基因频率 [MAF] <0.0001）编码变异（病例中为 6.1%，对照中为 2.0%；P = 0.046；OR 3.3；95%置信区间 [CI] 1.0-11.1），但病例中也观察到低频（MAF<0.001 和 >0.0001）变异的富集，其中 1 个变异（SCN5A：p.Arg965Cys）在 4.6%的泰国 BrS 患者中检测到，而在对照中为 0.5%（P = 0.015；OR 9.8；95%CI 1.2-82.3）。
泰国 BrS 的遗传基础包括广泛的变异频率和效应大小。如先前在欧洲和日本人群中所示，SCN5A 和 HEY2 附近的常见变异与泰国人群中的 BrS 相关，证实了这两个主要 BrS 基因座在跨种族中的可转移性。
