The relationship between HMGCR genetic variation, alternative splicing, and statin efficacy.
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.
Medina
Marisa Wong
MW
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. mwmedina@chori.org
D017398:Alternative Splicing; D005091:Exons; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases