期刊
PHARMACOGENETICS AND GENOMICS
卷 22, 期 12, 页码 858-867出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0b013e32835a450b
关键词
CYP2B6; efavirenz; HIV; pharmacogenomics; pharmacokinetics
资金
- AIDS Clinical Trials Group
- National Institute of Allergy and Infectious Diseases [AI-068634, AI-038855, AI-54999, BRS-ACURE-06-00140-T001, AI-051966, AI-069419, UL1 RR-024996, AI-069472, AI-062435, AI-069439, TR-000011, AI-068636, AI-038858]
- NIH National Institute of Allergy and Infectious Diseases (NIAID) [AI-069419, AI-069472, AI-069439, AI-069532, AI-069484, AI-069432, AI-069450, AI-069495, AI-069434, AI-069424, AI-069467, AI-069423, AI-069513, AI-069477, AI-069465, AI-069502, AI-069474, AI-069501, AI-069418, AI-069494, AI-069471, AI-069511, AI-069452]
- NIH National Center for Research Resources (NCRR) [RR-000046, RR-000425, RR-025747, RR-025777, RR-025780, RR-024996, RR-024160, RR-023561, RR-024156]
- Bristol-Myers Squibb
- Abbott
- Merck
- Pfizer
- ViiV
- Gilead
- Janssen
- Gilead Sciences
- Schering-Plough
- The NIH National Institute of Allergy and Infectious Diseases (NIAID) [AI-038858, AI-069428, AI-069556, AI-069415, AI-032782, AI-046376, AI-046370, AI-034853, AI-027661, AI-025859, AI-069470, AI-027675, AI-073961, AI-050410, AI-045008, AI-050409, AI-072626, AI-069447, AI-027658, AI-027666, AI-058740, AI-025868]
Objectives Prior candidate gene studies have associated CYP2B6 516G -> T [rs3745274] and 983T -> C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics. Materials and methods Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (C-min) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry. Results Among 856 individuals, CYP2B6 516G -> T was associated with efavirenz estimated C-min (P = 8.5 x 10(-41)). After adjusting for CYP2B6 516G -> T, CYP2B6 983T -> C was associated (P = 9.9 x 10(-11)). After adjusting for both CYP2B6 516G -> T and 983T -> C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P = 4.4 x 10(-15)). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5 x 10(-8). In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated C-min. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms. Conclusion Three CYP2B6 polymorphisms were independently associated with efavirenz estimated C-min at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization. Pharmacogenetics and Genomics 22:858-867 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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