Population-specific association between ABCG2 variants and tophaceous disease in people with gout

Abstract

BackgroundTophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout.MethodsParticipants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status.ResultsCompared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02–1.51) for rs2231142 and 1.33 (1.01–1.74) for rs10011796, p < 0.05 for both). The effect of rs2231142 was limited to participants of Māori or Pacific ancestry (OR 1.50 (1.14–1.99), p = 0.004), with a significant effect observed in those of Western Polynesian ancestry only (OR 1.71 (1.07–2.72), p = 0.017). The rs10011796 risk allele was strongly associated with tophi in the Western Polynesian group (OR 3.76 (1.61–8.77), p = 0.002), but not in the Eastern Polynesian group (OR 0.87 (0.52–1.46), p = 0.60) nor in the non-Polynesian group (OR 1.16 (0.81–1.66), p = 0.32). The ABCG2 associations persisted in the Western Polynesian group after adjusting for serum urate, creatinine, and disease duration, and when including both ABCG2 variants in the regression models.ConclusionsVariation in ABCG2 function may play a role in the development of tophaceous disease in some populations with high prevalence of severe gout.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1254-8) contains supplementary material, which is available to authorized users.

The impact of diuretic use and ABCG2 genotype on the predictive performance of a published allopurinol dosing tool

“…ABCG2 genotype had an important impact on dose predictions. Our results align with published work where the T-allele has also been associated with poor allopurinol response [14], hyperuricemia [15], and the presence of tophi [16]. The inference is that patients carrying the T-allele will have a reduced efflux of urate and will therefore require higher allopurinol doses to achieve the target urate response.…”

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

“…Although the T allele has a similar gout risk effect size, it is fivefold more prevalent in Western Polynesian (Table 1) and will, therefore, have a greater impact on this population. It is also a known risk factor for tophus in the presence of gout in Western Polynesian (OR = 1.66) but not in Eastern Polynesian (OR = 0.91) [39]. The striking interaction of the risk T allele of rs2231142 with rs10011796 in promoting gout in the presence of HU is observed in Western Polynesian but not Eastern Polynesian sample sets (Table 5).…”

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

“…Although the T allele has a similar gout risk effect size, it is 5-fold more prevalent in Western Polynesian (Table 1) and will, therefore, have a greater impact on this population. It is also a known risk factor for tophus in the presence of gout in Western Polynesian (OR=1.66) but not in Eastern Polynesian (OR=0.91) (39). The striking interaction of the risk T allele of rs2231142 with rs10011796 in promoting gout in the presence of HU is observed in Western Polynesian but not Eastern Polynesian sample sets (Table 5).…”