TY - JOUR
T1 - The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression
AU - Sakiyama, Masayuki
AU - Matsuo, Hirotaka
AU - Shimizu, Seiko
AU - Nakashima, Hiroshi
AU - Nakamura, Takahiro
AU - Nakayama, Akiyoshi
AU - Higashino, Toshihide
AU - Naito, Mariko
AU - Suma, Shino
AU - Hishida, Asahi
AU - Satoh, Takahiro
AU - Sakurai, Yutaka
AU - Takada, Tappei
AU - Ichida, Kimiyoshi
AU - Ooyama, Hiroshi
AU - Shimizu, Toru
AU - Shinomiya, Nariyoshi
N1 - Funding Information:
We thank all the participants involved in this study. We are especially indebted to K. Gotanda, Y. Morimoto, J. Abe, M. Miyazawa, H. Inoue, Y. Kawamura, T. Chiba and Y. Takada for genetic analysis. We are indebted to A. Tokumasu, K. Wakai and N. Hamajima, for sample collection. We also thank M. Hosoyamada and T. Hosoya for their helpful discussion. This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan including the MEXT KAKENHI (Grant numbers 221S0001, 221S0002, 25293145, 22689021, 25670307), the Ministry of Health, Labour and Welfare of Japan, the Ministry of Defense of Japan, the Kawano Masanori Memorial Foundation for Promotion of Pediatrics, and the Gout Research Foundation of Japan.
Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.
PY - 2016/1/29
Y1 - 2016/1/29
N2 - 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).
AB - 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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U2 - 10.1038/srep20148
DO - 10.1038/srep20148
M3 - Article
C2 - 26821810
AN - SCOPUS:84956558201
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 20148
ER -