title: ABCG2/BCRP dysfunction as a major cause of gout.
abstract: Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 ± 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 × 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with ≤1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 × 10(-21)). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population.
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. hmatsuo@ndmc.ac.jp
authors: Hirotaka
authors: H
authors: Matsuo
authors: Tappei
authors: T
authors: Takada
authors: Kimiyoshi
authors: K
authors: Ichida
authors: Takahiro
authors: T
authors: Nakamura
authors: Akiyoshi
authors: A
authors: Nakayama
authors: Hiroshi
authors: H
authors: Suzuki
authors: Tatsuo
authors: T
authors: Hosoya
authors: Nariyoshi
authors: N
authors: Shinomiya
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001692:Biological Transport; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006073:Gout / Q000097:blood / Q000150:complications / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000150:complications / Q000235:genetics; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014527:Uric Acid / Q000097:blood
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D014527:Uric Acid