ReseaRch aRticle ISSN 1462-2416 Pharmacogenomics (2009) 10 (11), 1743–1751 10.2217/PGS.09.105 © 2009 Future Medicine Ltd part of 1743 Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males Statins are widely used in the treatment of hyper- cholesterolemia. They inhibit the enzyme HMG- CoA reductase, which is involved in the synthesis of cholesterol. Inhibition results in a decrease in total cholesterol and LDL-cholesterol levels and a reduction in morbidity and mortality [1] . The reduction in triglyceride levels is small. In general, statins are safe and effective in lower- ing total and LDL-cholesterol levels, although they have the potential to cause myopathy and rhabdomyolysis [2] . Transporters are involved in the carriage of drugs and other substances over membranes. One of these transporters is P-glycoprotein (P-gp), which is involved in the eflux of drugs such as digoxin and ciclosporin [3,4] . P-gp is mainly found in the liver, small intestine and blood–brain barrier [5,6] . The hepatic expression of P-gp is stronger in males than in females [7] . Simvastatin, a commonly used statin, is a substrate for P-gp [8–10] . Reduced P-gp activity may result in increased plasma levels due to a decrease in simvastatin eflux out of the body in the small intestine and liver. The P-gp transporter is encoded by the ABCB1 gene, with gene location 7q21.12, previously known as the MDR1 gene. Many SNPs have been identified in the ABCB1 gene [101] . It is established that three SNPs (C1236T, G2677T/A and C3435T) affect the drug transporter function of P-gp, although it is unclear whether these SNPs are also asso- ciated with the degree of cholesterol-lowering effect during simvastatin therapy [5,11–13] . P-gp expression is stronger in males than in females and therefore we tested the hypothesis that the effect of SNPs in ABCB1 is stronger in males than in females. In the analyses, we stratiied for gender to show this potential difference. In this population-based cohort study of people aged 55 years and older, we analyzed the association between these three SNPs and haplotypes in the ABCB1 gene and reduction in total cholesterol and LDL-cholesterol levels after start of simvastatin therapy. Materials & methods  Setting Data for these analyses were obtained from the Rotterdam Study, a prospective population- based cohort study of 7983 Caucasians aged Aims: The cholesterol-lowering drug simvastatin is a substrate for P-glycoprotein (P-gp). P-gp, encoded by ABCB1 , is an eflux transporter and genetic variation in ABCB1 is associated with drug levels and response. We examined the Rotterdam Study, which is a population-based cohort study of people aged 55 years and older, to see whether the C1236T, G2677T/A and C3435T polymorphisms and haplotypes in the ABCB1 gene are associated with the total cholesterol and low-density lipoprotein cholesterol-lowering effect of simvastatin. Materials & methods: We identiied 85 incident simvastatin users, for whom a cholesterol measurement both before and after the start of simvastatin therapy was available. Associations between the ABCB1 gene variants and reductions in cholesterol levels were analyzed. In our analysis we stratiied for gender, because the level of P-gp expression in the liver is higher in men than in women. Results: The three ABCB1 polymorphisms were associated with total cholesterol reduction in the whole population. In men, both the 1236/2677/3435 TTT haplotype and the CGT haplotype were associated with larger reductions in total cholesterol (TTT: -0.40 mmol/l, 95% CI: -0.63 to -0.17; CGT: -0.44 mmol/l, 95% CI: -0.77 to -0.11) and low-density lipoprotein cholesterol levels (TTT: -0.51 mmol/l, 95% CI: -0.81 to -0.22; CGT: -0.53 mmol/l, 95% CI: -0.92 to -0.15) than the reference CGC haplotype. In women, genetic variation in the ABCB1 gene was not associated with total and low-density lipoprotein cholesterol levels. Conclusion: Male simvastatin users with the ABCB1 1236/2677/3435 TTT and CGT haplotype have larger reductions in total cholesterol and low-density lipoprotein cholesterol compared with the wild-type CGC haplotype. For women, no associations were found. KEYWORDS: ABCB1 protein  cholesterol  hypercholesterolemia  male  pharmacogenetics  simvastatin Mathijs L Becker 1 , Loes E Visser 1 , Ron HN van Schaik 1,2 , Albert Hofman 1,3 , André G Uiterlinden 1,3 & Bruno HCh Stricker 1,3,4† † Author for correspondence: 1 Erasmus MC, PO Box 2040, 3000 CA Roterdam, The Netherlands Tel.: +31 703 406 793 Fax: +31 703 406 707 b.stricker@erasmusmc.nl 2 STAR Medical Diagnosic Center, Roterdam, The Netherlands 3 Member of the Netherlands Consorium on Healthy Aging, Leiden/Roterdam, The Netherlands 4 Drug Safety Unit, Inspectorate for Healthcare, The Hague, The Netherlands For reprint orders, please contact: reprints@futuremedicine.com