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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 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 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 (Pmeta = 2.5E-?03). CONCLUSION:These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

SUBMITTER: Wrigley R

PROVIDER: S-EPMC7069001 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Wrigley Rebekah R Phipps-Green Amanda J AJ Topless Ruth K RK Major Tanya J TJ Cadzow Murray M Riches Philip P Tausche Anne-Kathrin AK Janssen Matthijs M Joosten Leo A B LAB Jansen Tim L TL So Alexander A Harré Hindmarsh Jennie J Stamp Lisa K LK Dalbeth Nicola N Merriman Tony R TR

Arthritis research & therapy 20200312 1

<h4>Background</h4>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.<h4>Methods</h4>We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New ...[more]

PMID: 32164793

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Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .

Dataset Information

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

Publications

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

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