The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression - PubMed (original) (raw)

Clinical Trial

doi: 10.1038/srep20148.

Hirotaka Matsuo 1, Seiko Shimizu 1, Hiroshi Nakashima 3, Takahiro Nakamura 4, Akiyoshi Nakayama 1, Toshihide Higashino 1, Mariko Naito 5, Shino Suma 5, Asahi Hishida 5, Takahiro Satoh 2, Yutaka Sakurai 3, Tappei Takada 6, Kimiyoshi Ichida 7, Hiroshi Ooyama 8, Toru Shimizu 9 10, Nariyoshi Shinomiya 1

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Clinical Trial

The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression

Masayuki Sakiyama et al. Sci Rep. 2016.

Abstract

Urate transporter 1 (URAT1/SLC22A12), a urate transporter gene, is a causative gene for renal hypouricemia type 1. Among several reported nonsynonymous URAT1 variants, R90H (rs121907896) and W258X (rs121907892) are frequent causative mutations for renal hypouricemia. However, no case-control study has evaluated the relationship between gout and these two variants. Additionally, the effect size of these two variants on serum uric acid (SUA) levels remains to be clarified. Here, 1,993 primary gout patients and 4,902 health examination participants (3,305 males and 1,597 females) were genotyped with R90H and W258X. These URAT1 variants were not observed in any gout cases, while 174 subjects had the URAT1 variant in 2,499 health examination participants, respectively (P = 8.3 × 10(-46)). Moreover, in 4,902 health examination participants, the URAT1 nonfunctional variants significantly reduce the risk of hyperuricemia (P = 6.7 × 10(-19); risk ratio = 0.036 in males). Males, having 1 or 2 nonfunctional variants of URAT1, show a marked decrease of 2.19 or 5.42 mg/dl SUA, respectively. Similarly, females, having 1 or 2 nonfunctional variants, also evidence a decrease of 1.08 or 3.89 mg/dl SUA, respectively. We show that URAT1 nonfunctional variants are protective genetic factors for gout/hyperuricemia, and also demonstrated the sex-dependent effect size of these URAT1 variants on SUA (P for interaction = 1.5 × 10(-12)).

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Conflict of interest statement

Yes, there is potential competing interest: H.M., T.T. and N.S. have a patent pending based on the work reported in this paper. The other authors declare that they have no conflict of interest.

Figures

Figure 1

Figure 1. Changes of serum uric acid levels of URAT1 nonfunctional alleles in health examination participants.

4,753 health examination participants, who received no medication for gout and/or hyperuricemia, were analyzed. Among 3,158 male participants (left, black bars), 0, 1 and 2 nonfunctional alleles (R90H or W258X) were detected in 2,982, 174 and 2 males, respectively. Among 1,595 female participants (right, grey bars), 0, 1 and 2 nonfunctional alleles (R90H or W258X) were detected in 1,529, 63 and 3 females, respectively. Serum uric acid (SUA) levels of participants having 0, 1 and 2 nonfunctional alleles were shown in each sex. The sex-dependent effect size of SUA decrease by nonfunctional alleles (arrow) was also shown. All bars are expressed as means ± SEM.

References

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