Functional non-synonymous variants of ABCG2 and gout risk

Stibůrková, Blanka; Pavelcová, Kateřina; Závada, Jakub; Petrů, Lenka; Šimek, Pavel; Čepek, Pavel; Pavlı́ková, Markéta; Matsuo, Hirotaka; Merriman, Tony R.; Pavelka, Karel

doi:10.1093/rheumatology/kex295

Cited by 67 publications

(71 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the common Q141K variant, there are numerous other uncommon and rare missense variants in ABCG2, mostly detected by resequencing ABCG2 exons in people with gout. These variants tend, as does 141K, to reduce the urate transport ability of ABCG2 [52]; they associate with gout [52,53] and, including 141K, associate with an earlier age-of-onset of gout [52,54]. The effect size on gout is similar to that of 141Kincreasing risk two to threefold [53].…”

Section: Discussionmentioning

confidence: 83%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 83%

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The T153M (458 C.T; rs753759474) polymorphism was shown to cause decreased ABCG2 expression, resulting in decreased resistance to , due to reduced efflux activity (Mizuarai et al, 2004;Yoshioka et al, 2007;Stiburkova et al, 2017). A recent study linked T153M to gout induction, along with the nearby polymorphism R147W.…”

Section: Less Well-studied Snps In the Nbdmentioning

confidence: 99%

Polymorphisms of the Multidrug Pump ABCG2: A Systematic Review of Their Effect on Protein Expression, Function, and Drug Pharmacokinetics

2018

View full text Add to dashboard Cite

The widespread expression and polyspecificity of the multidrug ABCG2 efflux transporter make it an important determinant of the pharmacokinetics of a variety of substrate drugs. Null ABCG2 expression has been linked to the Junior blood group. Polymorphisms affecting the expression or function of ABCG2 may have clinically important roles in drug disposition and efficacy. The most well-studied single nucleotide polymorphism (SNP), Q141K (421C>A), is shown to decrease ABCG2 expression and activity, resulting in increased total drug exposure and decreased resistance to various substrates. The effect of Q141K can be rationalized by inspection of the ABCG2 structure, and the effects of this SNP on protein processing may make it a target for pharmacological intervention. The V12M SNP (34G>A) appears to improve outcomes in cancer patients treated with tyrosine kinase inhibitors, but the reasons for this are yet to be established, and this residue's role in the mechanism of the protein is unexplored by current biochemical and structural approaches. Research into the less-common polymorphisms is confined to in vitro studies, with several polymorphisms shown to decrease resistance to anticancer agents such as SN-38 and mitoxantrone. In this review, we present a systematic analysis of the effects of ABCG2 polymorphisms on ABCG2 function and drug pharmacokinetics. Where possible, we use recent structural advances to present a molecular interpretation of the effects of SNPs and indicate where we need further in vitro experiments to fully resolve how SNPs impact ABCG2 function.

show abstract

“…In addition to the common Q141K variant there are numerous other uncommon and rare missense variants in ABCG2, mostly detected by resequencing ABCG2 exons in people with gout. These variants tend, as does 141K, to reduce the urate transport ability of ABCG2 (52), they associate with gout (52,53) and, including 141K, associate with an earlier age-of-onset of gout (52, 54). The effect size on gout is similar to that of 141K – increasing risk 2-3 fold (53).…”

Section: Discussionmentioning

confidence: 99%

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

Wrigley

Phipps‐Green

Topless

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundThe 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.MethodsWe 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.ResultsIn Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR=1.85, P=3.8E-21 and ORmeta =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 (ORmeta=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 (PHet=0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and the genetically-independent 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 positively associated with flare frequency in Polynesian (Pmeta=2.5E-03).ConclusionThese data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

show abstract

Functional non-synonymous variants of ABCG2 and gout risk

Abstract: Genetic variants of ABCG2, common and rare, increased the risk of gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout.

Cited by 67 publications

References 32 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

Polymorphisms of the Multidrug Pump ABCG2: A Systematic Review of Their Effect on Protein Expression, Function, and Drug Pharmacokinetics

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

Contact Info

Product

Resources

About