Validation and Disease Risk Assessment of Previously Reported Genome-Wide Genetic Variants Associated with Brugada Syndrome: SADS-TW BrS Registry.

Background - Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest (SCA). Several BrS or ECG traits-related single nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in Caucasian 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 (BrS-PRS) 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's proportional hazards model was utilized to evaluate the associations between each particular SNP, the collective BrS-PRS, and clinical outcomes. Results - Of the 88 previously reported SNPs, 22 were validated in Taiwanese BrS patients (P<0.05). Of the 22 SNPs, 2 (rs10428132, rs9388451) were linked with susceptibility to BrS, 10 were SNPs previously reaching genome-wide significance, and 10 were SNPs associated with electrocardiogram traits. For the 3 most commonly reported SNPs, disease risk increased consistently with the number of risk alleles (OR 3.54, Ptrend = 1.38 * 10-9 for 5 risk alleles versus 1). Similar patterns were observed in both SCN5A mutation+ (OR 3.66, Ptrend = 0.049) and SCN5A mutation- (OR 3.75, Ptrend = 8.54 * 10-9) subgroups. Furthermore, BrS patients without SCN5A mutations had more risk alleles than BrS patients with SCN5A mutations regardless of the range of PRS. Three SNPs (rs4687718, rs7784776, rs2968863) showed significant associations with the composite outcome (SCA plus syncope, HR 2.13, 1.48, 0.41; P=0.02, 0.006, 0.008, respectively). Conclusions - Our findings suggested that some SNPs associated with BrS or electrocardiogram traits exist across multiple populations. The cumulative risk of the BrS-related SNPs is similar to that in Caucasian BrS patients, but it appears to correlate with the absence of SCN5A mutations.