ABCG2 contributes to the development of gout and hyperuricemia in a genome-wide association study

Chen, Chung‐Jen; Tseng, Chia‐Chun; Yen, Jeng‐Hsien; Chang, Jan‐Gowth; Chou, Wen‐Cheng; Chu, Hou‐Wei; Chang, Shun‐Jen; Liao, Wei‐Ting

doi:10.1038/s41598-018-21425-7

Cited by 60 publications

(55 citation statements)

References 44 publications

(42 reference statements)

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“…Deficiency in ABCG2 generates dysfunctional mitochondria [25] and reduced copy number of mitochondrial DNA associates with increased risk of gout in NZ Polynesian [26]. The observation that colchicine is able to rescue the 141K trafficking defect [23], the proposal that autophagy machinery and the inflammasome interact in the innate immune response [27], and evidence for association of ABCG2 rs2231142 with gout in the presence of HU in East Asian populations [28][29][30], suggests that ABCG2 may be important in gout beyond its established role in elevating urate levels. This hypothesis is further supported by the observation that the effect size of ABCG2 on urate in Europeans and Japanese is 58% and 73% that of SLC2A9, the most influential urate locus [4,31], respectively, yet the effect size of ABCG2 on gout is consistently larger than that of SLC2A9 [4,5,32].…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

et al. 2020

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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 1699 European gout cases and 14,350 normouricemic (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 Polynesian (OR meta = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E − 06 ), however significantly weaker than ABCG2 rs2231142 141K (P Het = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E − 06 ). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (P meta = 2.5E − 03 ). Conclusion: These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

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Section: Introductionmentioning

confidence: 99%

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

et al. 2020

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“…Furthermore, the SNP was direction‐consistent with gout in both white and black participants (Dehghan et al, ). Subsequent genetic studies in other populations, such as Han Chinese (Yang et al, ; Chen et al, ), Japanese (Matsuo et al, ), and Caucasians (Zhang et al, ), provided compelling evidences for the association of ABCG2 with the susceptibility of hyperuricemia. Recently, the study of Abcg2 ‐knockout mice has revealed that the extra‐renal urate excretion decrease induced by ABCG2 dysfunction also caused hyperuricemia (Ichida et al, ).…”

Section: Introductionmentioning

confidence: 99%

IL‐1β functionally attenuates ABCG2 and PDZK1 expression in HK‐2 cells partially through NF‐ĸB activation

Chen

Shen

et al. 2019

Cell Biology International

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Long‐standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL‐1β. However, how IL‐1β, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL‐1β could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK‐2 cells by real‐time PCR and Western‐blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL‐1β also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF‐κB pathway partly dampened the inhibitory effect of IL‐1β on ABCG2, indicating that IL‐1β reduced the ABCG2 expression partially through the NF‐ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL‐1β, which is dependent on the NF‐κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL‐1β, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.

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“…In a Taiwanese study of people with gout, the 141K allele was associated with tophi in both Han and Aboriginal Taiwanese populations (Cleophas et al, 2017). The polymorphism rs2231142 in the ABCG2 gene, which causes a Glu141Lys amino acid substitution, accounted for 0.57% of the variation in serum urate, and a functional study of rs2231142 showed that it causes a 53% reduction in the rate of ABCG2-mediated urate transport compared with wildtype ABCG2 (Chen et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Risk Factor Analysis for Gout in the Latvian Population

Nagle

Luksa

Moisejevs

et al. 2020

Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.

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Communicated by Aivars LejnieksGout (Gr. podagra) is a multifactorial pathology, which means that both genetic and environmental factors play a role in the aetiology of the disease. For these reasons, revealing risk factors could be of very high importance in prevention and treatment of gout. In the present study, we found that a major role in gout predisposition is played by specific alleles in the ABCG2 gene. The study used survey data for 43 gout patients and 99 healthy control individuals who were genotyped for rs2231142. It was found that allelic variant rs2231142 in the ABCG2 gene had the strongest association with gout. Among other co-factors studied, sex, and increased body mass index were associated with gout.

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ABCG2 contributes to the development of gout and hyperuricemia in a genome-wide association study

Cited by 60 publications

References 44 publications

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

IL‐1β functionally attenuates ABCG2 and PDZK1 expression in HK‐2 cells partially through NF‐ĸB activation

Risk Factor Analysis for Gout in the Latvian Population

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