Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).
In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011).
Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
从16个中心(n=312)招募了来自携带SCN5A突变的队列的自发1型模式或阳性/阴性药物攻击的受试者。在rs11708996,rs10428132和rs9388451这两个队列中研究了先前与BrS相关的全基因组意义的单核苷酸多态性。假定BrS-GRS的加性线性遗传模型(6个单核苷酸多态性风险等位基因)。
在总人口中(n=312),BrS-GRS≥4个风险等位基因对BrS表型的比值比为4.15([95%CI,1.45-11.85];P=0.0078)。在SCN5A阳性个体中(n=258),BrS-GRS≥4个风险等位基因的比值比为2.35([95%CI,0.89-6.22];P=0.0846)。在SCN5A阴性亲属中(n=54),BrS-GRS≥4个等位基因的比值比为22.29([95%CI,1.84-269.30];P=0.0146)。在E1784K-SCN5A阳性家庭成员中(n=79),携带≥4个风险等位基因的比值比=5.12([95%CI,1.93-13.62];P=0.0011).
在SCN5A家族中,常见的遗传变异与BrS表型的可变表达有关,部分解释不完全外显率和基因型阴性表型阳性个体。SCN5A突变基因型和BrS-GRS与BrS表型相关,但关联强度根据SCN5A突变的存在和功能丧失的严重程度而变化.