Candidate‐Gene Study of Functional Polymorphisms inSLCO1B1andCYP3A4/5and the Cholesterol‐Lowering Response to Simvastatin

Abstract

Cholesterol-lowering response to 40mg simvastatin daily for 6 weeks was examined for associations with common genetic polymorphisms in key genes affecting simvastatin metabolism (CYP3A4 and CYP3A5) and transport (SLCO1B1). In Whites (n = 608), SLCO1B1 521C was associated with lesser reductions of total and low-density lipoprotein cholesterol. Associations between SLCO1B1 521C and cholesterol response were not detected in African-Americans (n = 333). Associations between CYP3A4*22 or CYP3A5*3 and cholesterol response were not detected in either race, and no significant race-gene or gene-gene interactions were detected. As several of the analyses may have been underpowered (especially the analyses in the African American cohort), the findings not suggesting an association should not be considered conclusive and warrant further investigation. The finding regarding SLCO1B1 521C in Whites was consistent with several previous reports. SLCO1B1 521C resulted in a diminished cholesterol-lowering response, but a marginal effect size limits utility for predicting simvastatin response.

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

“…One meta-analysis suggests that the SLCO1B1 -521T>C polymorphism is a risk factor for statininduced ADRs, especially for simvastatin users; however, no significant association for the -388A>G polymorphism is apparent [114]. Cholesterol-lowering response to statins show ethnic differences [115,116]. In white patients, SLCO1B1 521C is associated with smaller reductions in total cholesterol and low-density lipoprotein cholesterol in patients treated with simvastatin.…”

“…In white patients, SLCO1B1 521C is associated with smaller reductions in total cholesterol and low-density lipoprotein cholesterol in patients treated with simvastatin. No associations between SLCO1B1 521C and cholesterol response are detected in African Americans, and no associations between CYP3A4*22 or CYP3A5*3 and cholesterol response are observed in other populations [116]. Most studies convey that PGx testing prior to treatment with statins is effective in reducing ADRs in patients with mutant SLCO1B1 [117].…”

Association between SLCO1B1 polymorphism distribution frequency and blood lipid level in Chinese adults

“…OATP1B1 has a role in the transport of a wide variety drugs, such as statins. Several pharmacogenetic studies and metaanalyses have focused on the potential contribution of SLCO1B1 variations in the response to statins or repaglinide, but little attention has been paid to whether SLCO1B1 is involved in lipoprotein transformation and metabolic process that affects individual lipid levels [4][5][6][7][8][9][10][11][12][13][14][15]. We therefore hypothesised that common variants of SLCO1B1 have an impact into levels of serum lipids, and so by extension, a potential role in risk assessment.…”