Pleiotropic effect of ABCG2 in gout: involvement in serum urate levels and progression from hyperuricemia to gout (original) (raw)
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Background The ABCG2 Q141K ( rs2231142 ) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. Methods We analysed 1,699 European gout cases and 14,350 normourciemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. Results In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR=1.85, P =3.8E -21 and OR meta =1.85, P =1.3E -03 , respectively). There was evidence for an effect of 141K in determining HU in European (OR=1.56, P =1.7E -18 ) but not in P...
Rheumatology, 2010
Objectives. Recent genome-wide association and functional studies have shown that the ABCG2 gene encodes for a urate transporter, and a common causal ABCG2 variant, rs2231142, leads to elevated uric acid levels and prevalent gout among Whites and Blacks. We examined whether this finding is observed in a Japanese population, since Asians have a high reported prevalence of the T-risk allele. Methods. A total of 3923 Japanese people from the Circulatory Risk in Communities Study aged 40-90 years were genotyped for rs2231142. Associations of the rs2231142 variant with serum uric acid levels and prevalence of gout and hyperuricaemia were examined. Results. The frequency of the T-risk allele was 31% in this Japanese sample. Multivariable adjusted mean uric acid levels were 7-9 mmol/l higher for TG and TT than GG carriers (P-additive = 0.0006). The multivariable-adjusted odds ratio (OR) of prevalent gout was 1.37 (95% CI 0.68, 2.76) for TG and 4.37 (95% CI 1.98, 9.62) for TT compared with the GG carriers (P-additive = 0.001). When evaluating the combined outcome of hyperuricaemia and gout, the respective ORs were 1.40 (95% CI 1.04, 1.87) for TG and 1.88 (95% CI 1.23, 2.89) for TT carriers. The population attributable risk was 29% for gout and 19% for gout and/or hyperuricaemia. Conclusions. The association of the causal ABCG2 rs2231142 variant with uric acid levels and gout was confirmed in a sample of Japanese ancestry. Our study emphasizes the importance of this common causal variant in a population with a high risk allele frequency, especially as more Japanese adopt a Western lifestyle with a concomitant increase in mean serum uric acid levels.
American Journal of Epidemiology, 2013
A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10 −67 , P = 3.98 × 10 −5 , P = 6.97 × 10 −9 , and P = 5.33 × 10 −4 in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10 −10 , P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10 −80) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10 −12). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
A comprehensive analysis of the association of common variants of ABCG2 with gout
Scientific Reports
The objective of the present study was to determine whether there was an association between single nucleotide polymorphisms (SNPs) in ABCG2 and gout. We recruited 333 participants including 210 patients with gout and 123 controls and genotyped 45 SNPs in both cohorts. We found that 24 SNPs in ABCG2 are susceptibility loci associated with gout. Haplotype analysis revealed five blocks across the ABCG2 locus were associated with an increased risk of gout with odds ratios (ORs) from 2.59-3.17 (all P < 0.0001). A novel finding in the present study was the identification of rs3114018 in block 3 and its association with increased gout risk. We found that the rs2231142T allele in block 2 and the rs3114018C-rs3109823T (C-T) risk haplotype in block 3 conferred the greatest evidence of association to gout risk (P = 1.19 × 10 −12 and P = 9.20 × 10 −11 , respectively). Our study provides an improved understanding of ABCG2 variations in patients with gout and, as shown by haplotype analysis, that ABCG2 may have a role in gout susceptibility. Gout is an arthritis that is characterized by elevated serum uric acid level, recurrent acute arthritis, and chronic tophaceous gout 1-3. Epidemiological studies from several countries have found that the incidence and prevalence of gout may be increasing 1-5. Moreover, women comprise approximately 5% of all patients with gout, but the incidence of gout in women has doubled in the past 20 years 3-5. An increased serum uric acid concentration is because of either overproduction or under excretion of uric acid 1. In over 90 percent of patients, gout is caused by the under excretion of uric acid 1. Genome-wide association studies (GWAS) that scan the genome for common genetic variants associated with gout have greatly advanced our medical knowledge 2, 6. The majority of genes associated with serum urate levels or gout are involved in the renal urate-transport system. Gout is a complex disease with a multifactorial etiology involving genetic and environmental factors 4, 5. Several molecules are associated with gout and hyperuricemia in various populations 7-20. Moreover, several GWASs on gout and hyperuricemia have been performed to date, and more than 50 loci have been identified 2, 7, 9, 14, 18-20. Recent GWAS have identified substantial associations between SNPs in ABCG2 and uric acid concentration and gout in different ethnic groups 2, 7. ABCG2 (also known as BCRP) is located at a gout-susceptibility locus on chromosome 4q22, which was previously identified in several genome-wide linkage studies of gout 7, 12, 20. ABCG2 mediates urate secretion in proximal renal tubule cells, the intestine, and the liver 2, 8, 9. Furthermore, several studies have proposed that variations in ABCG2 may be important in the etiology of gout 2, 7-17, 21. To verify further the impact of polymorphisms in genes related to gout, we studied common genetic variability in ABCG2 using a case-control study to clarify the association between SNPs or haplotypes at ABCG2 with the risk of gout in a Chinese population. Methods Study population. All enrolled patients were recruited at the Chang Gung Memorial Hospital (CGMH) at Tao-Yuan County (Taiwan) from February 2013 to March 2016. The study was approved by the local ethics
2010
Genetic variation in ABCG2 (rs2231142, Q141K), encoding a uric acid transporter, is associated with gout in diverse populations. The aim of this study was to examine a role for ABCG2 in gout susceptibility in New Zealand Mā ori, Pacific Island and Caucasian samples. Patients (n 5 185, 173 and 214, for Mā ori, Pacific Island and Caucasian, respectively) satisfied the American College of Rheumatology gout classification criteria. The comparison samples comprised 284, 129 and 562 individuals, respectively, without gout. rs2231142 was genotyped and stratification accounted for using genomic control markers. Association of the minor allele of rs2231142 with gout was observed in the Pacific Island samples (OR 5 2.80, P STRAT < 0.001 after accounting for effects of population structure), but not in the Mā ori samples (OR 5 1.08, P STRAT 5 0.70), with heterogeneity in association evident between the Mā ori and Pacific Island datasets (P HET 5 0.001). A similar dichotomy in association was observed when samples were stratified into Western (Tonga, Samoa, Niue, Tokelau) versus Eastern Polynesian (Mā ori, Cook Island) origin (OR 5 2.59, P STRAT < 0.001; OR 5 1.12, P STRAT 5 0.48, respectively; P HET 5 0.005). Association with gout was observed in the Caucasian samples (OR 5 2.20, P 5 3.2 3 10 28 ). Unlike SLC2A9, which is a strong risk factor for gout in both Mā ori and Pacific Island people, ABCG2 rs2231142 has a strong effect only in people of Western Polynesian ancestry. Our results emphasize the need to account for sub-population differences when undertaking biomedical genetic research in a group defined by a geographical region and shared ancestry but characterized by migratory events that create bottlenecks and altered genetic structure in the founder populations.
ABCG2 contributes to the development of gout and hyperuricemia in a genome-wide association study
Scientific reports, 2018
Although many genome-wide association studies (GWASs) of hyperuricemia or gout have been reported, the related genetic factors and the mechanisms from hyperuricemia to gouty attack remain unclear. This study aimed to identify genetic factors and pathogenesis of gout from hyperuricemia by genome-wide association study (GWAS). 747 gout patients, 747 hyperuricemia and 2071 age-matched controls were recruited and analyzed with Affymetrix 650 K chip to find the related genetic variants. The functions of the related genes were investigated in an endothelial cell (EC) with urate crystal stimulation. The GWAS results showed 36 SNPs to be strongly associated with gout compared to controls (all p-values < 10). Whereas the rs2231142 in ABCG2 gene had significant associations between gout and controls, between gout and hyperuricemia, and between hyperuricemia and controls (all p-values < 10), and the ORs were 4.34, 3.37 and 2.15 (all p-values < 0.001) after adjustment of potential conf...
Journal of Health Science and Medical Research (JHSMR), 2023
Objective: This study aimed to investigate whether the risk of gout was associated with the ABCG2 rs2231142 variant and how this was affected by metabolic parameters. Material and Methods: The subjects were selected from the genetic variations of urate transporter genes in hyperuricemia and gout in the Thai population (GUHGTH) study. Overall, 96 participants aged 30-60 years were included in the study. Adjusted odds ratio (AORs) of gout was analyzed using multiple logistic regression models and the effects of combinations of ABCG2 rs2231142 variants and metabolic parameters on gout were explored. Results: The TG and TT genotypes of ABCG2 rs2231142 and hyperglycemia were significantly associated with gout risk. The risk of gout was significantly increased by the combined association of ABCG2 rs2231142 and metabolic parameters obesity and hyperglycemia for the TG and TT genotypes compared to the GG genotype (wild-type genotype). Conclusion: In conclusion, the ABCG2 rs2231142 variant was found to be a genetic risk factor for gout in Thai men. Obesity and hyperglycemia combined with the ABCG2 rs2231142 risk allele contributed to an increase in the risk of gout. Further case-control studies with larger sample sizes should be performed to confirm the combinations of the ABCG2 rs2231142 variant, obesity, and hyperglycemia on the risk of gout.
Clinical and Experimental Medicine
Gout is a common crystal induced disease of high personal and social burden, characterised by severe arthritis and comorbidity if untreated. Impaired function of ABCG2 transporter is causative in gout and may be responsible for renal-overload type hyperuricemia. Despite its importance, there is limited information on how clinical parameters correlate with protein expression and that with genetic changes. Urate and clinical parameters of 78 gouty patients and healthy controls were measured among standardised circumstances from a Hungarian population. ABCG2 membrane expression of red blood cells was determined by flow cytometry-based method and SNPs of this protein were analysed by TaqMan-based qPCR. The prevalence of ABCG2 functional polymorphisms in gouty and control patients were 32.1 and 13.7%, respectively. Most common SNP was Q141K while one sample with R236X, R383C and the lately described M71V were found in the gouty population. These polymorphisms showed strong linkage with d...
Journal of Clinical Medicine
Gout is an inflammatory arthritis influenced by environmental risk factors and genetic variants. The common dysfunctional p.Q141K allele of the ABCG2 gene affects gout development. We sought after the possible association between the p.Q141K variant and gout risk factors, biochemical, and clinical determinants in hyperuricemic, gouty, and acute gouty arthritis cohorts. Further, we studied the correlation of p.Q141K allele and levels of pro-/anti-inflammatory cytokines. Coding regions of the ABCG2 gene were analyzed in 70 primary hyperuricemic, 182 gout patients, and 132 normouricemic individuals. Their genotypes were compared with demographic and clinical parameters. Plasma levels of 27 cytokines were determined using a human multiplex cytokine assay. The p.Q141K variant was observed in younger hyperuricemic/gout individuals (p = 0.0003), which was associated with earlier disease onset (p = 0.004), trend toward lower BMI (p = 0.056), and C-reactive protein (CRP, p = 0.007) but a hig...
Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus
Rheumatology, 2020
Objective The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. Methods Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. Results In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently i...