ABCMdb

PMID: 22132966

Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Suzuki H, Hosoya T, Shinomiya N
ABCG2/BCRP dysfunction as a major cause of gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1117-28., [PubMed]

Sentences

No. Mutations Sentence Comment

11 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Two relatively frequent dysfunctional variants, Q126X and Q141K, were Received 29 May 2011; accepted 17 October 2011. Login to comment 18 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys 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 ). Login to comment 19 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment 20 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. Login to comment 38 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gln126* ABCG2 p.Gln126* ABCG2 p.Gln126* ABCG2 p.Gly268Arg 1119 ABCG2 : ATP binding casse e G2 SNP : single nucleo de polymorphism QTL : quan ta ve trait locus OR : odds ra o ABCG2 as a urate secre on transporter in humans Gene c analysis Func onal analysis ABCG2 muta on analysis of 90 hyperuricemic cases (all coding regions) ABCG2 muta ons (with amino acid altera ons) 6 muta ons c d Func onal analysis of urate transport via wild type ABCG2 (vesicle studies) a Iden fica on of urate transport ac vi es via ABCG2 b Func onal analysis of urate transport via mutated ABCG2 6 mutants e No effect (V12M) g Dysfunc onal genotype combina ons of ABCG2 as major causes of gout q Dysfunc onal SNP with high frequency (>30%) (Q141K) QTL analysis in 739 Japanese individuals h i j n Gout / hyperuricemia with ABCG2 homozygous, n = 2 heterozygous, n = 24 Loss of func on (Q126X, G268R, S441N, F506Sfs) Reduced func on (~50%) (Q141K) f p Genotype combina on analysis 10.1% of gout with ≤1/4 ABCG2 func on OR = 25.8, p = 3.39×10-21 o Haplotype analysis 13.5% of gout with disease haplotype OR = 5.97, p = 4.10×10-12 Associa on analysis of hyperuricemia (Q126X) OR = 3.61, p = 2.91× 10-7 l m Associa on analysis of gout (Q126X) OR = 4.25, p =3.04 × 10-8 Genotyping of nonfunc onal SNP (Q126X) hyperuricemia, n=228 k FIGURE 1 Flowchart for molecular-function-based clinicogenetic (FBCG) analysis of gout patients with ABCG2 polymorphic variants. Login to comment 45 ABCG2 p.Gln141Lys Quantitative trait locus (QTL) analysis of SUA concentrations was performed with genotyping of Q141K in 739 Japanese individuals. Login to comment 53 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg Using the site-directed mutagenesis technique, we constructed ABCG2 mutants (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment 65 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg The following six nonsynonymous mutations, including three SNPs, were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Figure 2A). Login to comment 70 ABCG2 p.Gln141Lys Results are expressed as means ± S.D. (C) Quantitative trait locus (QTL) analysis of ABCG2 Q141K and serum uric acid levels. Login to comment 71 ABCG2 p.Gln141Lys "C/C," "C/A," and "A/A" indicate wild-type subjects, heterozygous mutation carriers, and homozygous mutation carriers of Q141K, respectively. Login to comment 76 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Val12Met ABCG2 p.Gln126* ABCG2 p.Gln126* Maekawa et al.[17] reported that V12M, Q126X, and Q141K are quite common in the Japanese population, and allele frequencies for these SNPs were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment 77 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Gln126* Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[17] we estimated that the frequencies of Japanese individuals with these minor alleles were 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment 79 ABCG2 p.Gln141Lys ABCG2 p.Ser441Asn ABCG2 p.Gln126* ABCG2 p.Gly268Arg Among six mutants, ATP-dependent urate transport was reduced by approximately half (46.7%) in one mutant, Q141K, and was nearly eliminated in four mutants, Q126X, G268R, S441N, and F506SfsX4 (Figure 2B). Login to comment 80 ABCG2 p.Val12Met The V12M variant did not show any changes in urate transport compared to wild-type ABCG2. Login to comment 81 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 Dysfunction Increases SUA In a random sample of 739 Japanese individuals, QTL analysis of SUA with the high-frequency dysfunctional variant Q141K revealed that SUA significantly increased as the number of minor alleles of Q141K increased (p = 6.60 × 10-5 ), and the corrected p value adjusted for sex is 2.02 × 10-6 (Figure 2C). Login to comment 83 ABCG2 p.Gln141Lys Different from SUA, Q141K had no significant association with other clinical characteristics such as age, body mass index, or sex. Login to comment 85 ABCG2 p.Gln126* ABCG2 Dysfunction Increases Gout Risk Additional genotyping of ABCG2 SNPs for 228 Japanese men with hyperuricemia (including 161 men with gout) served to identify Q126X homozygous (n = 2) and heterozygous (n = 24) mutations. Login to comment 86 ABCG2 p.Gln126* Two patients with Q126X homozygous mutations showed very high SUA (> 10 mg/dl) before they were treated for hyperuricemia/gout. Login to comment 88 ABCG2 p.Gln126* Through the association study, Q126X was revealed to increase the risk of hyperuricemia (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment 89 ABCG2 p.Gln126* ABCG2 p.Gln126* Among the 161 gout patients, Q126X homozygous (n = 1) and heterozygous (n = 21) mutations were found, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment 90 ABCG2 p.Gln141Lys The half-functional SNP Q141K also increased gout risk (OR, 2.23; 95% CI, 1.75-2.87; p = 5.54 × 10-11 ). Login to comment 91 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment 92 ABCG2 p.Gln126* The haplotype with Q126X markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with nonrisk haplotypes. Login to comment 93 ABCG2 p.Gln141Lys Q141K is assigned to another independent risk haplotype. Login to comment 94 ABCG2 p.Gln126* Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment 95 ABCG2 p.Gln126* Thus, the Q126X mutation of the ABCG2 gene is identified as a major cause of primary gout. Login to comment 96 ABCG2 p.Gln126* Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment 97 ABCG2 p.Val12Met We also found that V12M is exclusively assigned to a nonrisk haplotype. Login to comment 98 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Because Q126X and Q141K are assigned to different risk haplotypes, nonfunctional and half-functional, respectively, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function. Login to comment 106 ABCG2 p.Gln126* We also demonstrated that nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment 110 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Together with P-glycoprotein 21.4% 45.3% 23.3% 10.1% 50.8% 35.6% 12.7% 0.9% other gout risks gout no function Q126X T/T Q141K C/C Full function C/C C/C 3/4 function 1/2 function C/C C/C T/C A/C A/A C/C Gout patients Normal control SUA ≤ 7.0 mg/dl 1/4 function T/C A/C 25.8-fold gout risk ≥3.02-fold gout risk (n = 865) (n = 161) FIGURE 3 ABCG2 transport dysfunction as a major gout risk. Login to comment 111 ABCG2 p.Gln141Lys ABCG2 p.Gln126* Genotype combinations of Q126X and Q141K are divided into several groups based on estimated ABCG2 transport functions. Login to comment 125 ABCG2 p.Gln126* [14] Our approach (Figure 1) revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment 126 ABCG2 p.Gln126* ABCG2 p.Gln126* Different from the rare Mendelian disorders described above, the disease haplotype carrying the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X is a major mutation causing gout. Login to comment 134 ABCG2 p.Gln141Lys They also found that Q141K was associated with self-reported gout in Caucasians (OR, 1.74; 95% CI, 1.51-1.99), which is consistent with our finding from clinically diagnosed Japanese gout patients. Login to comment 135 ABCG2 p.Gln141Lys ABCG2 p.Gln126* A meta-analysis of GWAS of European descent also showed that the nine loci, including GLUT9 and ABCG2, influence SUA,[11] which confirms the findings of Dehghan et al.[10] In this study, we identified several nonfunctional ABCG2 mutations, including Q126X, which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment 138 ABCG2 p.Gln141Lys Woodward et al.[19] and we[2] independently found a urate transport ability via ABCG2 to transport urate and characterized the effects of a half-functional variant Q141K using different methods. Login to comment