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

Abstract

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.

The Epidemiology and Genetics of Hyperuricemia and Gout across Major Racial Groups: A Literature Review and Population Genetics Secondary Database Analysis

“…The ABCG2 gene is strongly associated with SU levels, early-onset gout, and the progression from HU to gout [ 25 , 49 , 50 ]. The encoded protein, ATP-binding cassette superfamily G member 2 (ABCG2), is expressed in the gastrointestinal tract, kidney, liver, and functions as a urate efflux transporter.…”

Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank

“…27 A smaller study using candidate gene hypothesis reported nominal association for ABCG2 polymorphism and gout vs. hyperuricaemia. 29 The only previous gout vs. hyperuricaemia GWAS was conducted in a Japanese population and reported rs7927466 in CNTN5, rs9952962 in MIR302F, and a suggestive locus rs12980365 in ZNF724 that do not affect SU. 10 Although rs7927466 is not included in the UK Biobank genotype platform, it is covered by its proxy SNP rs7942264 (r 2 =1) that did not show an association with gout; neither did rs12980365.…”

Polymorphisms of the genes ABCG2, SLC22A12 and XDH and their relation with hyperuricemia and hypercholesterolemia in Mexican young adults

“…The first corresponds to the exchange of a glutamine for a lysine at position 141 of an adenosine triphosphate (ATP)-binding cassette transporter subfamily G member 2 ( ABCG2 ). This exchange predisposes individuals to hyperuricemia ( Nakashima et al , 2020 ; Wrigley et al ., 2020 ). A frequency of 0.25 for the risk for T allele was found, a slightly lower prevalence than that reported in Asian and New Zealand populations ( Kim et al , 2015 ; Liu et al , 2020b ; Toyoda et al , 2019 ).…”