OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

Akasaka Central Clinic Tokyo Japan

Center for Genomic Medicine Kyoto University Graduate School of Medicine Kyoto Japan

Data Science Division Data Coordinating Center Department of Advanced Medicine Nagoya University Hospital Nagoya Aichi Japan

Department of Biochemisty University of Otago Dunedin New Zealand

Department of Bioinformatics and Genomics Graduate School of Advanced Preventive Medical Sciences Kanazawa University Kanazawa Ishikawa Japan

Department of Defense Medicine National Defense Medical College Tokorozawa Saitama Japan

Department of Environmental and Preventive Medicine Jichi Medical University School of Medicine Shimotsuke Tochigi Japan

Department of General Medicine National Defense Medical College Tokorozawa Saitama Japan

Department of Genome Science School of Dentistry Aichi Gakuin University Nagoya Aichi Japan

Department of Genomic Medicine Research Institute National Cerebral and Cardiovascular Center Suita Osaka Japan

Department of Geriatric Medicine Graduate School of Medical Sciences Kyushu University Fukuoka Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Saitama Japan

Department of International Island and Community Medicine Kagoshima University Graduate School of Medical and Dental Sciences Kagoshima Japan

Department of Medical Biochemistry Kurume University School of Medicine Kurume Fukuoka Japan

Department of Oral Epidemiology Hiroshima University Graduate School of Biomedical and Health Sciences Hiroshima Japan

Department of Pathophysiology and Therapy in Chronic Kidney Disease Jikei University School of Medicine Minato ku Tokyo Japan

Department of Pathophysiology Tokyo University of Pharmacy and Life Sciences Hachioji Tokyo Japan

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pharmacy the University of Tokyo Hospital Tokyo Japan

Department of Preventive Medicine and Public Health National Defense Medical College Tokorozawa Saitama Japan

Department of Preventive Medicine Faculty of Medicine Saga University Saga Japan

Department of Preventive Medicine Institute of Health Biosciences the University of Tokushima Graduate School Tokushima Japan

Department of Preventive Medicine Nagoya University Graduate School of Medicine Nagoya Aichi Japan

Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Osaka Japan

Department of Surgery National Defense Medical College Tokorozawa Saitama Japan

Department of Urology National Defense Medical College Tokorozawa Saitama Japan

Division of Human Genetics Department of Integrated Genetics National Institute of Genetics Mishima Shizuoka Japan

Division of Inflammation Biology Institute for Enzyme Research Tokushima University Tokushima Japan

Division of Kidney and Hypertension Department of Internal Medicine Jikei University School of Medicine Minato ku Tokyo Japan

Institute of Rheumatology Prague Czech Republic

Kyoto Industrial Health Association Kyoto Japan

Laboratory for Mathematics National Defense Medical College Tokorozawa Saitama Japan

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Kanagawa Japan

Laboratory of Bioresponse Regulation Graduate School of Pharmaceutical Sciences Osaka University Suita Osaka Japan

Laboratory of Statistical Immunology Immunology Frontier Research Center Osaka University Suita Osaka Japan

Medical Squadron Air Base Group Western Aircraft Control and Warning Wing Japan Air Self Defense Force Kasuga Fukuoka Japan

Midorigaoka Hospital Takatsuki Osaka Japan

Nagase Clinic Tokyo Japan

RIKEN Center for Integrative Medical Sciences Yokohama Kanagawa Japan

Ryougoku East Gate Clinic Tokyo Japan

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