OP0047\u2005A GENOME-WIDE ASSOCIATION STUDY IDENTIFIED NOVEL LOCI ASSOCIATED WITH THE PROGRESSION FROM ASYMPTOMATIC HYPERURICEMIA TO GOUT

Abstract

Background Gout is one of the commonest forms of inflammatory arthritis induced by monosodium urate (MSU) crystals that result from elevated serum uric acid (SUA) level. Thus far, we and others have performed genome-wide association studies (GWASs) of gout by comparing the genetic differences between gout cases and normouricemia controls1-3 and have identified gout risk loci such as ABCG2 and SLC2A9: these are similar results to those from GWASs of SUA. Meanwhile, not all hyperuricemia cases develop gout: the reason, we consider, is that there are at least two steps (Figure 1) by which normouricemic individuals develop gout. Objectives The first ever GWAS of clinically defined gout cases and asymptomatic hyperuricemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout, as distinct from loci causing SUA elevation. Methods We carried out a GWAS of 945 clinically-defined gout cases and 1,003 AHUA controls followed by two replication studies. In total, 2,860 gout cases and 3,279 AHUA controls (all Japanese males) were analyzed. And also, we compared the odds ratios (ORs) for each locus in the present GWAS (gout vs. AHUA) with those in the previous GWAS (gout vs. normouricemia). Furthermore, we investigated the effect of each locus on SUA using the results from our recent GWAS meta-analysis of SUA with a total of 121,745 Japanese subjects4. 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) (Figure 2). 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 vs. 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 (SUA) level. The effect of each locus on SUA using the results from our recent GWAS meta-analysis of SUA are consistent with those of the present study. Conclusion This first discovery of “AHUA to Gout” loci using a new GWAS strategy will lead to elucidation of the molecular mechanism of the last step of gout development and to the prevention of gout attacks in high-risk AHUA individuals.Figure 1 Two steps in the development of gout.Figure 2 Manhattan plots of the present GWAS (Gout vs. AHUA). References [1] Matsuo, H. et al. Ann Rheum Dis75, 652-9 (2016). [2] Nakayama, A. et al. Ann Rheum Dis76, 869-77 (2017). [3] Li, C. et al. Nat Commun6, 7041 (2015). [4] Nakatochi, M. et al. Commun Biol, in press. Disclosure of Interests Yusuke Kawamura: None declared, Hirofumi Nakaoka: None declared, Akiyoshi Nakayama: None declared, Yukinori Okada: None declared, Ken Yamamoto: None declared, Hiroshi Ooyama: None declared, Blanka Stiburkova: None declared, Tony Merriman Grant/research support from: Ardeabiosciences, Ironwood Pharmaceuticals, Consultant for: Ardeabiosciences, Ironwood Pharmaceuticals, Masahiro Nakatochi: None declared, Kenji Wakai: None declared, Michiaki Kubo: None declared, Kimiyoshi Ichida: None declared, Nariyoshi Shinomiya: None declared, Hirotaka Matsuo: None declared