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Abstract：
Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations.
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.
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.
摘要：
Brugada综合征（BrS）的特征在于1型BrugadaECG模式。在20％的BrS家族中发现了SCN5A的致病性罕见变异（突变），其中观察到不完全的外显率和基因型阴性的表型阳性个体。E1784K-SCN5A是鉴定出的最常见的SCN5A突变。我们确定了BrS遗传风险评分（BrS-GRS）和SCN5A突变类型与具有SCN5A突变的BrS家族中BrS表型的关联。
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.
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.
