Krauss Ronald M, Mangravite Lara M, Smith Joshua D, Medina Marisa W, Wang Dai, Guo Xiuqing, Rieder Mark J, Simon Joel A, Hulley Steven B, Waters David, Saad Mohammed, Williams Paul T, Taylor Kent D, Yang Huiying, Nickerson Deborah A, Rotter Jerome I
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Circulation. 2008 Mar 25;117(12):1537-44. doi: 10.1161/CIRCULATIONAHA.107.708388. Epub 2008 Mar 10.
Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response.
Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (-1.23+/-0.04 mmol/L, n=209, versus -1.45+/-0.06 mmol/L, n=117; P=0.0008) and percent response (-36.9+/-1.0% versus -40.6+/-1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (-28.2+/-4.9%, n=12 H2+H7 carriers, versus -41.5+/-0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites.
HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.
使用3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抑制剂即他汀类药物，可通过降低血浆低密度脂蛋白胆固醇（LDL-C）浓度来降低心血管疾病风险。然而，LDL-C反应存在个体差异，且受多种因素影响，包括种族血统，与白人相比，黑人的反应减弱。我们推测，编码HMGCR的基因中的单核苷酸多态性，胆固醇合成中的一种限速酶以及他汀类药物的直接酶作用靶点，导致了他汀类药物反应的差异。
对24名黑人及23名白人的HMGCR进行基因组重测序，共鉴定出79个单核苷酸多态性。选择11个单核苷酸多态性来标记常见的连锁不平衡簇。在326名黑人和596名白人中，检测这些单核苷酸多态性及其推断出的常见单倍型与血浆LDL-C以及辛伐他汀治疗（40mg/d，共6周）后LDL-C反应的相关性。与未携带任何一种单倍型的黑人参与者相比，携带H7和/或H2的黑人基线LDL-C显著降低（P=0.0006），LDL-C反应显著减弱，通过绝对反应测量（-1.23±0.04mmol/L，n=209，对比-1.45±0.06mmol/L，n=117；P=0.0008）以及百分比反应（-36.9±1.0%对比-40.6±1.3%；P=0.02），但在白人中未观察到单倍型效应。同时携带H2和H7的个体LDL-C百分比反应最低，其中除一人外均为黑人（-28.2±4.9%，n=12名H2+H7携带者，对比-41.5±0.5%，n=650名H2/H7非携带者；P=0.001）。H7和/或H2非携带者的LDL-C反应在黑人和白人之间无差异。
HMGCR基因多态性与血浆LDL-C降低以及对辛伐他汀的LDL-C反应相关，且这些效应在黑人中最为明显。
