Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants.
OBJECTIVE
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.


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 (Cmin) 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 Cmin (P=8.5×10). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P=9.9×10). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms.


CONCLUSIONS
Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin 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.
Center for Human Genetics Research bDepartments of Medicine, Pharmacology, Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37204, USA.
Emily R
ER
Holzinger
Benjamin
B
Grady
Marylyn D
MD
Ritchie
Heather J
HJ
Ribaudo
Edward P
EP
Acosta
Gene D
GD
Morse
Roy M
RM
Gulick
Gregory K
GK
Robbins
David B
DB
Clifford
Eric S
ES
Daar
Paul
P
McLaren
David W
DW
Haas
D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics*; D002985:Clinical Protocols; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D056726:Genetic Association Studies; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz