先前报道的与布鲁加达综合征相关的全基因组遗传变异的验证和疾病风险评估：SADS-TW BrS 登记处。
Validation and Disease Risk Assessment of Previously Reported Genome-Wide Genetic Variants Associated With Brugada Syndrome: SADS-TW BrS Registry.
机构信息
Cardiovascular Center, Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei (J.-M.J.J., Y.-B.L., C.-Y.J.C., L.-Y.L., W.-J.C., C.-C.Y., H.-C.H., L.-T.H., L.-P.L.).
Institute of Epidemiology and Preventive Medicine, Department of Public Health (Q.-Y.Y., A.C., T.-P.L.), National Taiwan University, Taipei.
出版信息
Circ Genom Precis Med. 2020 Aug;13(4):e002797. doi: 10.1161/CIRCGEN.119.002797. Epub 2020 Jun 3.
BACKGROUND
Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and the BrS-polygenic risk score in predicting cardiac events.
METHODS
We genotyped 190 unrelated BrS patients using the TWB Array, and Taiwan Biobank was used as controls. SNPs not included in the array were imputed by IMPUTE2. Cox proportional hazards model was used to evaluate the associations between each particular SNP, the collective BrS-polygenic risk score, and clinical outcomes.
RESULTS
Of the 88 previously reported SNPs, 22 were validated in Taiwanese BrS patients (<0.05). Of the 22 SNPs, 2 (rs10428132 and rs9388451) were linked with susceptibility to BrS, 10 were SNPs previously reaching genome-wide significance, and 10 were SNPs associated with ECG traits. For the 3 most commonly reported SNPs, disease risk increased consistently with the number of risk alleles (odds ratio, 3.54; =1.38×10 for 5 risk alleles versus 1). Similar patterns were observed in both mutation+ (odds ratio, 3.66; =0.049) and mutation- (odds ratio, 3.75; =8.54×10) subgroups. Furthermore, BrS patients without mutations had more risk alleles than BrS patients with mutations regardless of the range of polygenic risk scores. Three SNPs (rs4687718, rs7784776, and rs2968863) showed significant associations with the composite outcome (sudden cardiac arrest plus syncope, hazard ratio, 2.13, 1.48, and 0.41; =0.02, 0.006, and 0.008, respectively).
CONCLUSIONS
Our findings suggested that some SNPs associated with BrS or ECG traits exist across multiple populations. The cumulative risk of the BrS-related SNPs is similar to that in white BrS patients, but it appears to correlate with the absence of mutations.
背景
Brugada 综合征（BrS）是一种具有心律失常风险增加的遗传性疾病，其发生心源性猝死的风险较高。通过对白人患者进行全基因组关联研究，已鉴定出与 BrS 或心电图特征相关的单核苷酸多态性（SNP）。本研究旨在对台湾人群中的 BrS 患者进行这些 SNP 的验证，评估风险等位基因的累积效应以及 BrS 多基因风险评分对预测心脏事件的作用。
方法
本研究共纳入了 190 例无血缘关系的 BrS 患者，使用 TWB 芯片进行基因分型，同时利用台湾生物银行作为对照组。未包含在芯片中的 SNP 通过 IMPUTE2 进行推断。使用 Cox 比例风险模型评估每个特定 SNP、整体 BrS 多基因风险评分与临床结局之间的关系。
结果
在台湾 BrS 患者中，对 88 个先前报道的 SNP 进行了验证（<0.05）。在这 22 个 SNP 中，有 2 个（rs10428132 和 rs9388451）与 BrS 的易感性相关，10 个为先前达到全基因组显著性的 SNP，10 个与心电图特征相关。对于报道最广泛的 3 个 SNP，随着风险等位基因数量的增加，疾病风险也随之增加（优势比，3.54；=1.38×10 与 5 个风险等位基因相比，1）。这种模式在 突变+（优势比，3.66；=0.049）和 突变-（优势比，3.75；=8.54×10）亚组中均有观察到。此外，无论多基因风险评分范围如何，没有 突变的 BrS 患者携带的风险等位基因数量均多于有 突变的 BrS 患者。3 个 SNP（rs4687718、rs7784776 和 rs2968863）与复合终点（心源性猝死加晕厥）显著相关（危险比，2.13、1.48 和 0.41；=0.02、0.006 和 0.008）。
结论
本研究结果表明，一些与 BrS 或心电图特征相关的 SNP 存在于多个人群中。BrS 相关 SNP 的累积风险与白人 BrS 患者相似，但似乎与 突变的缺失有关。
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