SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).
SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).
复制标题
SCARB1 基因变异与高密度脂蛋白胆固醇和高脂蛋白组合的表型相关 (a)。
DOI：
10.1161/circgenetics.116.001402
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Becker,LewisC
中科院分区：
文献类型：
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作者：
Yang,Xiaoping;Sethi,Amar;Yanek,LisaR;Knapper,Cathy;Nordestgaard,BørgeG;Tybjærg-Hansen,Anne;Becker,DianeM;Mathias,RasikaA;Remaley,AlanT;Becker,LewisC
BackgroundSR-B1 (scavenger receptor class B type 1), encoded by the geneSCARB1, is a lipoprotein receptor that binds both high-density lipoprotein (HDL) and low-density lipoprotein. We reported that SR-B1 is also a receptor for lipoprotein (a) (Lp(a)), mediating cellular uptake of Lp(a) in vitro and promoting clearance of Lp(a) in vivo. Although genetic variants inSCARB1are associated with variations in HDL level, noSCARB1variants affecting Lp(a) have been reported.Methods and ResultsIn an index subject with high levels of HDL cholesterol and Lp(a),SCARB1was sequenced and demonstrated a missense mutation resulting in an S129L substitution in exon 3. To follow up, 2 cohorts (GeneSTAR, the family-based Genetic Study of Atherosclerosis Risk [n=543], and CCHS, the population-based Copenhagen City Heart Study [n=5835]) were screened for combined HDL cholesterol and Lp(a) elevations. Subjects with the extreme phenotype (HDL >80 mg/dL and Lp(a) >100 nmol/L in GeneSTAR, n=8, and >100 mg/dL in CCHS, n=9) underwent sequencing ofSCARB1exons; 15 of 18 from the combined population demonstrated genetic variants, including rare or uncommon missense or splice site mutations in 9 and homozygous synonymous variants in 6. Functional studies with 4 of theSCARB1variants (c.386C>T, c.631-14T>G, c.4G>A, and c.631-53mC>T & c.726+55mCG>CA) showed decreased receptor function in vitro.ConclusionsHumanSCARB1gene variants are associated with a new lipid phenotype, characterized by high levels of both HDL cholesterol and Lp(a).SCARB1exonic variants often result in diminished function of translated SR-B1 via reduced binding/intracellular transport of Lp(a).
