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 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 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.

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

“…A similar pattern of hyperuricemia has been reported in the rs475688, rs3825016, and rs11726117 polymorphisms of the SLC22A12 gene encoding for URAT1 which results in renal hypouricemia type 1 [41,42]. A similar outcome has been observed with the rs2231142 single nucleotide polymorphism of the BCRP gene encoding for ABCG2 in addition to defective intestinal urate excretion [43,44]. Rare cases of OAT4 or OAT10 gene mutations have been identified in the literature as potential etiological factors for hyperuricemia [45,46].…”

The development from hyperuricemia to gout: key mechanisms and natural products for treatment

“…ABCG2, an ATP-driven efflux pump, has a significant role in urate secretion in the proximal tubule and intestine. In addition to SLC2A9 and ABCG2, GWASs of patients with gout have identified a few other gout risk loci, which were consistent with those found in GWASs of HUA [14][15][16] (Table 1).…”

“…Further study revealed that macrophage-derived platelet-activating factor (PAF) is involved in the non-inflammatory phagocytosis of MSU crystals by human blood monocyte-derived differentiated macrophages [36] . PAF is regarded as a potent mediator of immune responses that regulates various processes, including cytokine release and phagocytosis [1,[15][16] . When stimulated with MSU crystals, in vitro differentiated macrophages were found to secrete PAF, whereas this secretion was absent in immature monocytes under the same stimulation.…”

The Epidemiology and Genetics of Hyperuricemia and Gout Across Major Racial Groups: A literature Review and Population Genetics Secondary Data Analysis

“…(7) The ABCG2 gene is strongly associated with SU levels, early-onset gout, and the progression from HU to gout. (41)(42)(43) The encoded protein, ATP-binding cassette superfamily G member 2 (ABCG2), is expressed in both the kidney and liver and functions as a urate e ux transporter. The genetic polymorphism rs2231142 (G>T) in ABCG2 leads to Glu141Lys amino acid change, which results in a reduced ABCG2mediated urate e ux activity and in ammation dysregulation via augmented IL-8 release (Table 1).…”