Dataset Information

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

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)).

SUBMITTER: Sakiyama M

PROVIDER: S-EPMC4731750 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Sakiyama Masayuki M Matsuo Hirotaka H Shimizu Seiko S Nakashima Hiroshi H Nakamura Takahiro T Nakayama Akiyoshi A Higashino Toshihide T Naito Mariko M Suma Shino S Hishida Asahi A Satoh Takahiro T Sakurai Yutaka Y Takada Tappei T Ichida Kimiyoshi K Ooyama Hiroshi H Shimizu Toru T Shinomiya Nariyoshi N

Scientific reports 20160129

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 ...[more]

PMID: 26821810

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Project description:OBJECTIVES:Human urate transporter 1 (URAT1) is a member of the organic anion transporter family (SLC22A12) that primarily regulates the renal tubular reabsorption of uric acid. This case-control study was designed to analyse whether hURAT1 might also be a candidate gene for hyperuricaemia or hypouricaemia. SETTING:We recruited 68 healthy volunteers and divided them into two groups: a normal uric acid group and a hyperuricaemia group. We analysed the sequence of the URAT1 gene and found five significant single nucleotide polymorphisms (SNPs). We then selected 900 male subjects from the 262,200 enrolled in the Korean Cancer Prevention Study-II (KCPS-II) cohort for further genetic analysis. PARTICIPANTS:DNA samples from 36 individuals with normal uric acid (<4.5?mg/dL) and 32 individuals with hyperuricaemia (>8.5?mg/dL) were sequenced. Five significant SNPs (rs7929627, rs75786299, rs3825017, rs11602903 and rs121907892) were identified. We then chose 900 subjects from the KCPS-II cohort consisting of 450 subjects with normal uric acid (UA <4.1?mg/dL) and 450 subjects with hyperuricaemia (UA >8.7?mg/dL). The groups were matched by age, body mass index, metabolic syndrome and use of anti-hypertensive medication. PRIMARY OUTCOME MEASURES:We compared the OR of the incidence of hyperuricaemia by URAT1 genotype. RESULTS:The strongest association with hyperuricaemia was observed for rs75786299 (IVS3+11A/G) with an OR of 32.05. rs7929627 (IVS7-103A/G) and rs3825017 (N82N) showed an association with hyperuricaemia with ORs of 2.56 and 2.29, respectively. rs11602903 (788A/T) and rs121907892 (W258X) were negatively correlated with hyperuricaemia with ORs of 0.350 and 0.447, respectively. Individuals carrying the GATAG haplotype (n=32)-a relatively common variant consisting of rs7929627, rs75786299 and rs3825017-showed the highest risk for hyperuricaemia with an OR of 92.23 (p=9.55×10(-3)). CONCLUSIONS:These results indicate that five newly described SNPs in the hURAT1 gene are significantly associated with uric acid level (4-2008-0318 and 4-2011-0277).

Dataset Information

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

Publications

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

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