Medina Marisa Wong
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
Discov Med. 2010 Jun;9(49):495-9.
Statins are a class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the enzyme which catalyzes the rate limiting step of cholesterol biosynthesis. Although numerous trials have demonstrated statin efficacy in the reduction of cardiovascular disease risk, there is substantial variation between individuals in the magnitude of plasma LDL-cholesterol reduction. Pharmacogenetic studies have identified HMGCR genetic variation associated with this inter-individual variation. Here we describe how these studies lead to the discovery that HMGCR alternative splicing of exon 13 is not only a marker, but also a determinant of statin efficacy; not only for the treatment of hypercholesterolemia, but also as a chemopreventive agent for colorectal cancer.
他汀类药物是一类降低胆固醇的药物，可抑制3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR），该酶催化胆固醇生物合成的限速步骤。尽管大量试验已证明他汀类药物在降低心血管疾病风险方面的疗效，但个体之间血浆低密度脂蛋白胆固醇降低的幅度存在很大差异。药物遗传学研究已确定与这种个体间差异相关的HMGCR基因变异。在此，我们描述这些研究如何导致发现外显子13的HMGCR可变剪接不仅是他汀类药物疗效的一个标志物，也是其决定因素；不仅用于治疗高胆固醇血症，还可作为结直肠癌的化学预防剂。
