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A common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility |
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| Authors: | Masayuki Sakiyama Hirotaka Matsuo Seiko Shimizu Toshinori Chiba Akiyoshi Nakayama Yuzo Takada Takahiro Nakamura Tappei Takada Emi Morita Mariko Naito Kenji Wakai Hiroki Inoue Seishiro Tatsukawa Junki Sato Kazumi Shimono Toshiaki Makino Takahiro Satoh Hiroshi Suzuki Yoshikatsu Kanai Nobuyuki Hamajima Yutaka Sakurai Kimiyoshi Ichida Toru Shimizu Nariyoshi Shinomiya |
| Institution: | 1. Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan 2. Department of Dermatology, National Defense Medical College, Tokorozawa, Japan 3. Laboratory for Biofunctions, The Central Research Institute, National Defense Medical College, Tokorozawa, Japan 4. Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Japan 5. Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan 6. Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan 7. Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan 8. Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan 9. Division of Bio-system Pharmacology, Department of Pharmacology, Osaka University, Osaka, Japan 10. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan 11. Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Japan 12. Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan 13. Midorigaoka Hospital, Takatsuki, Japan |
| Abstract: | Gout is a common disease resulting from hyperuricemia which causes acute arthritis. Recently, genome-wide association studies revealed an association between serum uric acid levels and a common variant of leucine-rich repeat-containing 16A (LRRC16A) gene. However, it remains to be clarified whether LRRC16A contributes to the susceptibility to gout. In this study, we investigated the relationship between rs742132 in LRRC16A and gout. A total of 545 Japanese male gout cases and 1,115 male individuals as a control group were genotyped. rs742132 A/A genotype significantly increased the risk of gout, conferring an odds ratio of 1.30 (95 % CI 1.05–1.60; p = 0.015). LRRC16A encodes a protein called capping protein ARP2/3 and myosin-I linker (CARMIL), which serves as an inhibitor of the actin capping protein (CP). CP is an essential element of the actin cytoskeleton, which binds to the barbed end of the actin filament and regulates its polymerization. In the apical membrane of proximal tubular cells in the human kidney, the urate-transporting multimolecular complex (urate transportsome) is proposed to consist of several urate transporters and scaffolding proteins, which interact with the actin cytoskeleton. Thus, if there is a CARMIL dysfunction and regulatory disability in actin polymerization, urate transportsome may be unable to operate appropriately. We have shown for the first time that CARMIL/LRRC16A was associated with gout, which could be due to urate transportsome failure. |
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