Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans
Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans
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DOI：
10.1172/jci37176
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发表时间：
2009-04-01
影响因子：
15.9
通讯作者：
Rader, Daniel J.
中科院分区：
文献类型：
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作者：
Edmondson, Andrew C.;Brown, Robert J.;Rader, Daniel J.
高密度脂蛋白胆固醇（HDL-C）的血浆浓度升高与动脉粥样硬化性心血管疾病的保护有关。动物模型表明，内皮脂肪酶（LIPG）的表达降低与HDL-C水平呈负相关，全基因组关联研究已确定LIPG变体与人类HDL-C水平相关。我们假设LIPG中的功能缺失突变可能导致HDL-C升高，因此对HDL-C水平升高的病例和HDL-C水平降低的对照组进行了LIPG外显子的深度重测序。我们确定了HDL-C升高病例特有的显著过量的非同义LIPG变体。体外脂肪酶活性测定表明，这些变体显着降低内皮脂肪酶活性。此外，5个队列的荟萃分析表明，低频率Asn 396 Ser变异与HDL-C升高显著相关，而常见的Thr 111 Ile变异则与HDL-C升高无关。功能分析证实，Asn 396 Ser变体在体外和体内都具有显著降低的脂肪酶活性，而Thr 111 Ile变体具有正常的脂肪酶活性。我们的研究结果证实LIPG功能缺失突变导致HDL-C水平升高，并支持抑制内皮脂肪酶可能是升高HDL-C的有效机制的观点。
Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.