Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease.
Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease.
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DOI：
10.1161/circgen.119.002871
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发表时间：
2020-10
期刊：
影响因子：
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通讯作者：
Kathiresan S
中科院分区：
文献类型：
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作者：
Nomura A;Emdin CA;Won HH;Peloso GM;Natarajan P;Ardissino D;Danesh J;Schunkert H;Correa A;Bown MJ;Samani NJ;Erdmann J;McPherson R;Watkins H;Saleheen D;Elosua R;Kawashiri MA;Tada H;Gupta N;Shah SH;Rader DJ;Gabriel S;Khera AV;Kathiresan S
家族性谷甾醇血症是一种罕见的孟德尔疾病，其特征是饮食固醇的高吸收和胆汁排泄减少。受影响的个体通常在atp结合盒转运体G5 （ABCG5）或G8 （ABCG8）基因中具有完全的遗传缺陷-纯合功能丧失（LoF）变异，并且血浆谷固醇和低密度脂蛋白胆固醇（LDL-C）水平显著升高。ABCG5或ABCG8部分遗传缺陷（发生在LoF变异的杂合携带者中）对LDL-C和冠状动脉疾病（CAD）风险的影响仍不确定。我们首先招募了9个谷固醇血症家族，确定了ABCG5或ABCG8的致病性LoF变异，并评估了这些ABCG5或ABCG8 LoF变异与血浆植物甾醇和脂质水平的关系。接下来，我们评估了CAD病例（n=29,321）与对照组（n=357,326）中ABCG5或ABCG8的LoF变异。我们测试了ABCG5或ABCG8中罕见的LoF变异与血脂和冠心病风险的关系。罕见LoF变异被定义为ABCG5或ABCG8中等位基因频率小于0.1%的蛋白截断变异。在谷固醇血症家族中，7个家系携带ABCG5致病性LoF变异，2个家系携带ABCG8致病性LoF变异。ABCG5或ABCG8的纯合子LoF变异导致谷甾醇和LDL-C显著升高。在这些谷甾醇血症家族中，ABCG5 LoF变异的杂合携带者与非携带者相比，谷甾醇和LDL-C水平升高。在大规模CAD病例对照队列中，ABCG5和ABCG8中罕见LoF变异的患病率分别约为0.1%。ABCG5杂合LoF变异携带者LDL-C水平显著升高（25 mg/dL； 95%可信区间[CI] 14 ~ 35； P=1.1×10−6），冠心病风险增加2倍（优势比2.06,95% CI 1.27 ~ 3.35； P=0.004）。相比之下，ABCG8杂合LoF携带者状态与LDL-C升高或冠心病风险无关。虽然家族性谷甾醇血症传统上被认为是一种隐性疾病，但我们观察到ABCG5中LoF变体的杂合携带者显著增加了谷甾醇和LDL-C水平，并使冠心病的风险增加了两倍。
Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency – homozygous loss-of-function (LoF) variants – in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8 – as occurs in heterozygous carriers of LoF variants – on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. We first recruited nine sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29,321) versus controls (n=357,326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% in ABCG5 or ABCG8. In sitosterolemia families, seven pedigrees harbored causative LoF variants in ABCG5 and two pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 were approximately 0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1×10−6) and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.