TY - JOUR T1 - GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 869 LP - 877 DO - 10.1136/annrheumdis-2016-209632 VL - 76 IS - 5 AU - Akiyoshi Nakayama AU - Hirofumi Nakaoka AU - Ken Yamamoto AU - Masayuki Sakiyama AU - Amara Shaukat AU - Yu Toyoda AU - Yukinori Okada AU - Yoichiro Kamatani AU - Takahiro Nakamura AU - Tappei Takada AU - Katsuhisa Inoue AU - Tomoya Yasujima AU - Hiroaki Yuasa AU - Yuko Shirahama AU - Hiroshi Nakashima AU - Seiko Shimizu AU - Toshihide Higashino AU - Yusuke Kawamura AU - Hiraku Ogata AU - Makoto Kawaguchi AU - Yasuyuki Ohkawa AU - Inaho Danjoh AU - Atsumi Tokumasu AU - Keiko Ooyama AU - Toshimitsu Ito AU - Takaaki Kondo AU - Kenji Wakai AU - Blanka Stiburkova AU - Karel Pavelka AU - Lisa K Stamp AU - Nicola Dalbeth AU - Eurogout Consortium AU - Yutaka Sakurai AU - Hiroshi Suzuki AU - Makoto Hosoyamada AU - Shin Fujimori AU - Takashi Yokoo AU - Tatsuo Hosoya AU - Ituro Inoue AU - Atsushi Takahashi AU - Michiaki Kubo AU - Hiroshi Ooyama AU - Toru Shimizu AU - Kimiyoshi Ichida AU - Nariyoshi Shinomiya AU - Tony R Merriman AU - Hirotaka Matsuo Y1 - 2017/05/01 UR - http://ard.bmj.com/content/76/5/869.abstract N2 - Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8).Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia. ER -