Pharmacogenetics of OATP transporters reveals that SLCO1B1 c.388A>G variant is determinant of increased atorvastatin response.
OBJECTIVE
The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated.


METHODS
One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot(®) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan(®) Real-time PCR.


RESULTS
Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3-8.0, p < 0.05).


CONCLUSIONS
SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.
Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil; E-Mails:  paulamsp@gmail.com  (P.M.S.P.);  viviansilbiger@hotmail.com  (V.N.S.);  fdallavecchia@yahoo.com.br  (F.D.V.G.);  malicewi@usp.br  (M.A.V.W.);  sisorkin@usp.br  (S.S.A.);  adluchessi@uol.com.br  (A.D.L.);  mhhirata@usp.br  (M.H.H.);  rosariohirata@usp.br  (R.D.C.H.).
Alice C
AC
Rodrigues
Paula M S
PM
Perin
Sheila G
SG
Purim
Vivian N
VN
Silbiger
Fabiana D V
FD
Genvigir
Maria Alice V
MA
Willrich
Simone S
SS
Arazi
Andre D
AD
Luchessi
Mario H
MH
Hirata
Marcia M S
MM
Bernik
Egidio L
EL
Dorea
Carla
C
Santos
Andre A
AA
Faludi
Marcelo C
MC
Bertolami
Antonio
A
Salas
Ana
A
Freire
Maria V
MV
Lareu
Christopher
C
Phillips
Liliana
L
Porras-Hurtado
Manuel
M
Fondevila
Angel
A
Carracedo
Rosario D C
RD
Hirata
D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000069059:Atorvastatin; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics*; D015810:Linkage Disequilibrium; D027381:Liver-Specific Organic Anion Transporter 1; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000627:therapeutic use*; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D000069059:Atorvastatin