Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
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DOI：
10.1126/science.aad3517
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发表时间：
2016-03-11
期刊：
影响因子：
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通讯作者：
Global Lipids Genetics Consortium
中科院分区：
文献类型：
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作者：
Zanoni P;Khetarpal SA;Larach DB;Hancock-Cerutti WF;Millar JS;Cuchel M;DerOhannessian S;Kontush A;Surendran P;Saleheen D;Trompet S;Jukema JW;De Craen A;Deloukas P;Sattar N;Ford I;Packard C;Majumder Aa;Alam DS;Di Angelantonio E;Abecasis G;Chowdhury R;Erdmann J;Nordestgaard BG;Nielsen SF;Tybjærg-Hansen A;Schmidt RF;Kuulasmaa K;Liu DJ;Perola M;Blankenberg S;Salomaa V;Männistö S;Amouyel P;Arveiler D;Ferrieres J;Müller-Nurasyid M;Ferrario M;Kee F;Willer CJ;Samani N;Schunkert H;Butterworth AS;Howson JM;Peloso GM;Stitziel NO;Danesh J;Kathiresan S;Rader DJ;CHD Exome+ Consortium;CARDIoGRAM Exome Consortium;Global Lipids Genetics Consortium
清道夫受体BI（SR-BI）是高密度脂蛋白胆固醇（HDL-C）的主要受体。在人类中，血浆中高含量的HDL-C与冠心病（CHD）的风险较低相关。去除Scarb 1的小鼠（SR-BI敲除小鼠）HDL-C水平显著升高，但矛盾的是，动脉粥样硬化增加。SR-BI对人类HDL代谢和CHD风险的影响尚不清楚。通过对328名血浆HDL-C水平极高的个体的脂质修饰基因编码区进行靶向测序，我们鉴定了SCARB 1（编码SR-BI的基因）中一种功能缺失变体的纯合子，其中亮氨酸取代了脯氨酸376（P376 L）。P376 L变体损害SR-BI的翻译后加工，并消除转染细胞、来自纯合受试者的诱导多能干细胞的肝细胞样细胞和小鼠中的选择性HDL胆固醇摄取。大量基于人群的研究显示，P376 L变异杂合子携带者的血浆HDL-C水平显著升高。P376 L携带者具有显著的HDL相关表型和CHD风险增加（比值比= 1.79，具有统计学显著性）。
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).