It is suggested that effect size

It is suggested that effect size of this SNP is greater in males. Indeed, sexual differences in the regulation of serum UA levels have been reported. Obesity is often accompanied by hyperuricemia, but few studies have addressed the association between obesity and genetic variants involved in UA metabolism. The degree of association between ABCG2 rs2231142 SNP and gout risk has been found to vary with ethnicity. In this study, we examined whether association between the ABCG2 SNPs and UA levels in a Taiwanese cohort is differentially regulated by sex and obesity.

Materials and methods

Results

Discussion
We confirmed association of the SNP rs2231142 with UA levels and hyperuricemia in a Taiwanese cohort, and found it predominantly in males. Furthermore, obesity alone determined serum UA levels regardless of ABCG2 genotypes or sex, and we were the first to find an association between the rs2231142-A allele and hyperuricemia in obese patients.
A previous study shows that serum UA concentration has a 63% heritability. Indeed, a meta-analysis identifies ABCG2 among nine loci associated with UA concentration. In these studies, rs2231142 is the only SNP consistently associated with both hyperuricemia and gout. We confirmed the association with hyperuricemia except in nonobese females.
Previous studies show substantial interaction between genotypes and sex on UA levels. For instance, rs2231142 is consistently associated with UA concentration and gout in males. Our data showed a similar interaction, as we found significant association between rs2231142 and UA levels in males.
We found significant association between rs2231142 and hyperuricemia in obese patients. In a mouse model of obesity, concentration of both ABCG2 and urate Obeticholic Acid transporter URAT1 increases significantly, suggesting a link between enhanced urate reabsorption and obesity-associated hyperuricemia. Although we did not measure ABCG2 or URAT1 concentration, UA concentration was higher in obese patients and was further enhanced in those carrying the rs2231142-A allele. We hypothesized that obesity readily reveals effect of rs2231142 on hyperuricemia.
We uncovered an extra layer of interaction between sex, obesity, and rs2231142 on UA levels. Our data showed rs2231142-A was not associated with UA levels in nonobese females. This difference might be due to specific physiological characteristics of the nonobese females other than that of estrogen, because it has been reported that estrogen does not increase renal clearance of serum UA in adult women. Regarding the female hormonal effect on UA levels, we did not observe significant differences between premenopausal and menopausal female subgroups (Supplementary Table 1). Alternatively, nonobesity may have ameliorated hyperuricemia in rs2231142-A-carrying females by compensating for reduced ABCG2 activities. Whether it is due to metabolic or additional hormonal effect awaits further investigation, and a larger sample size is needed to clarify the role of sex hormones on UA levels and hyperuricemia in female patients.

Limitation
Because of the relatively small sample size and high minor allele frequency of rs2231142 in this study (Supplementary Table 2), it might have had limited power to detect associations between rs2231142 and UA. Still, we were able to validate our results independently using multiple regressions adjusted for confounding factors (Supplementary Table 3). In addition, we also validated our results using multiple testing corrections including full scan permutations (p = 0.001 for 1000 permutations), Bonferroni adjustment and false discovery rate (FDR) calculations (rs2231142-C allele; both regression Bonferroni P and regression FDR = 5.7 × 10−4), thus strengthening the conclusion that rs2231142 is indeed associated with serum UA levels.

Conclusion
A reduction-of-function SNP rs2231142 in the ABCG2 gene is associated with hyperuricemia in a Taiwanese cohort. The genetic determinants Obeticholic Acid for hyperuricemia differ according to sex and obesity status. The rs2231142-A allele has significantly stronger association with hyperuricemia in male and obese patients.