Wen C C, Yee S W, Liang X, Hoffmann T J, Kvale M N, Banda Y, Jorgenson E, Schaefer C, Risch N, Giacomini K M
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
Clin Pharmacol Ther. 2015 May;97(5):518-25. doi: 10.1002/cpt.89. Epub 2015 Apr 6.
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.
导致痛风的高尿酸血症的一线治疗药物是别嘌醇。别嘌醇的治疗反应差异很大，许多使用者无法达到目标血清尿酸（SUA）水平。尚无全基因组关联研究（GWAS）探讨影响别嘌醇疗效的遗传因素。我们利用凯撒医疗集团成人健康与衰老遗传流行病学研究（GERA）队列中的2027名受试者，首先在最大的种族群体——非西班牙裔白人（NHW）受试者中，然后在分层跨种族荟萃分析中，对与别嘌醇相关的SUA降低进行了GWAS。编码外排泵BCRP的ABCG2与NHW受试者的SUA降低相关（P = 2×10⁻⁸），并且在荟萃分析中，一个错义等位基因（rs2231142）与反应降低相关（P = 3×10⁻⁷）。细胞中的同位素摄取研究表明，BCRP转运别嘌醇，并且ABCG2中的基因变异会影响这种转运。总体而言，这项首次关于别嘌醇反应的GWAS表明，ABCG2是对该药物反应的关键决定因素。
