title: 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)).
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.|Department of Dermatology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Laboratory for Mathematics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Higashino
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Naito
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Suma
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Asahi
authors.initials: A
authors.lastname: Hishida
authors.affiliation: Department of Dermatology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan.
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.affiliation: Ryougoku East Gate Clinic, 3-21-1 Ryougoku, Sumida-ku, Tokyo 130-0026, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ooyama
authors.affiliation: Midorigaoka Hospital, 3-13-1 Makami-cho, Takatsuki, Osaka 569-1121, Japan.|Kyoto Industrial Health Association, 67 Kitatsuboi-cho, Nishinokyo, Nakagyo-ku, Kyoto 604-8472, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D006073:Gout / Q000097:blood / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000097:blood*
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid
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