Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 66, Issue 1, Pages 80-85Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0000000000000246
Keywords
-
Funding
- NIH [K23 GM100372-03, L32 MD006365, U01 GM092655, U19 HL069757, R01 HL104133]
- American Heart Association [14POST20100054, 12POST10430005]
- Pharmacogenomics Research Network PARC (Pharmacogenomics and Risk of Cardiovascular Disease) Study [HL069757]
- National Center for Advancing Translational Sciences, Clinical and Translational Science Institute [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]
Ask authors/readers for more resources
Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (approximate to 1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available