title: Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer.
abstract: Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide.
authors.affiliation: Department of Medicine, Weill Cornell School of Medicine, New York, New York 10021, USA. stl2012@med.cornell.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Chao
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: Hedy
authors.initials: H
authors.lastname: Rennert
authors.forename: Mila
authors.initials: M
authors.lastname: Pinchev
authors.forename: Diana
authors.initials: D
authors.lastname: Dizon
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D000368:Aged; D017398:Alternative Splicing; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases