Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

Publisher: Wiley Country of Publication: United States NLM ID: 0372741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-6535 (Electronic) Linking ISSN: 00099236 NLM ISO Abbreviation: Clin Pharmacol Ther Subsets: MEDLINE

Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: St. Louis : C.V. Mosby

Area Under Curve* ; Atorvastatin*/pharmacokinetics ; Atorvastatin*/blood ; Cytochrome P-450 CYP3A*/genetics ; Cytochrome P-450 CYP3A*/metabolism ; Genome-Wide Association Study* ; Glucuronosyltransferase*/genetics ; Liver-Specific Organic Anion Transporter 1*/genetics ; Polymorphism, Single Nucleotide*; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Genotype ; Healthy Volunteers ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood ; Pharmacogenomic Variants ; LIM Domain Proteins/genetics ; Cytoskeletal Proteins/genetics

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ) of atorvastatin (P = 1.2 × 10 ^-10 ), 2-hydroxy atorvastatin (P = 4.0 × 10 ^-8 ), and 4-hydroxy atorvastatin (P = 2.9 × 10 ^-8 ). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC 0-∞ (P = 3.8 × 10 ^-8 ). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC 0-∞ (P = 3.9 × 10 ^-8 ). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC 0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10 ^-11 ) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC 0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10 ^-5 ) smaller atorvastatin AUC 0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10 ^-5 ) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].
(© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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282106 International ERC_ European Research Council

A0JWA85V8F (Atorvastatin)
EC 1.14.14.55 (CYP3A4 protein, human)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
EC 2.4.1.17 (Glucuronosyltransferase)
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
0 (Liver-Specific Organic Anion Transporter 1)
0 (SLCO1B1 protein, human)
EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A3)
0 (LPP protein, human)
0 (LIM Domain Proteins)
0 (Cytoskeletal Proteins)

Date Created: 20240317 Date Completed: 20240513 Latest Revision: 20240709

20240710

10.1002/cpt.3236

38493369