Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2015 May;97(5):518-25.
doi: 10.1002/cpt.89. Epub 2015 Apr 6.

Genome-wide Association Study Identifies ABCG2 (BCRP) as an Allopurinol Transporter and a Determinant of Drug Response

Affiliations
Free PMC article
Meta-Analysis

Genome-wide Association Study Identifies ABCG2 (BCRP) as an Allopurinol Transporter and a Determinant of Drug Response

C C Wen et al. Clin Pharmacol Ther. .
Free PMC article

Abstract

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Figures

Figure 1
Figure 1
Manhattan plot of association of SNPs with change in uric acid levels in response to allopurinol in (a) 1,492 patients with European ancestries or (b) all patients using a stratified transethnic meta-analysis. Meta-analysis was conducted combining individual associations of each of the four ethnic groups. Overall, this includes 1,607 non-Hispanic whites, 238 Asians, 84 African Americans, and 85 Hispanics. Gray dots are imputed SNPs. P-values > 0.05 were not plotted.
Figure 2
Figure 2
Cell growth of HEK293 cells after treatment with mitoxantrone for 72 hours to test transporter function. Cells were stably transfected with either empty vector, reference ABCG2, or ABCG2 containing the Q141K variant.
Figure 3
Figure 3
BCRP-mediated transport of allopurinol, oxypurinol, and pitavastatin. Cells stably transfected with empty vector or reference ABCG2 were incubated with (a) [3H]-allopurinol or (b) [3H]-oxypurinol with or without Ko-143, a selective BCRP inhibitor. BCRP is an efflux transporter, so BCRP transport would lead to a lower accumulation of allopurinol in the HEK293 cells. (c) rs2231142 affects BCRP transport of allopurinol and oxypurinol. Cells stably transfected with reference ABCG2 or the ABCG2 Q141K variant were incubated with [3H]-allopurinol or [3H]-oxypurinol. (d) Allopurinol and oxypurinol did not affect BCRP transport of pitavastatin. Cells stably transfected with reference ABCG2 were incubated with [3H]-pitavastatin with or without Ko143, allopurinol (0.5, 1, and 2 mM), or oxypurinol (0.5, 1, and 2 mM). Using Dunnett’s multiple comparison test, only cells incubated with Ko-143 (10 μM) was statistically significant from cells incubated with vehicle (P < 0.0001). Values +/− standard errors are shown in these figures.

Similar articles

See all similar articles

Cited by 28 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback