Genome-Wide Association Study of Clinically-Ascertained Gout and Subtypes Identifies Multiple Susceptibility Loci Including Transporter Genes

Hirotaka Matsuo¹, Akiyoshi Nakayama², Hirofumi Nakaoka³, Ken Yamamoto⁴, Masayuki Sakiyama⁵, Amara Shaukat⁶, Yu Toyoda⁷, Yukinori Okada⁸, Yoichiro Kamatani⁹, Masahiro Nakatochi¹⁰, Takahiro Nakamura⁵, Tappei Takada⁷, Hiroshi Nakashima⁵, Seiko Shimizu⁵, Makoto Kawaguchi⁵, Asahi Hishida¹¹, Kenji Wakai¹¹, Blanka Stiburkova¹², Karel Pavelka¹³, Lisa K. Stamp¹⁴, Nicola Dalbeth¹⁵, Tatsuo Hosoya¹⁶, Michiaki Kubo⁹, Hiroshi Ooyama¹⁷, Toru Shimizu¹⁸, Kimiyoshi Ichida¹⁹, Tony R. Merriman²⁰ and Nariyoshi Shinomiya²¹, ¹Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan, ²Dept Integrative Physiol, National Defense Med College, Tokorozawa, Japan, ³National Inst Genet, Mishima, Japan, ⁴Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan, ⁵National Defense Med College, Tokorozawa, Japan, ⁶Univ Otago, Dunedin, New Zealand, ⁷Univ Tokyo Hosp, Tokyo, Japan, ⁸Osaka University, Osaka, Japan, ⁹Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan, ¹⁰Nagoya Univ Hosp, Nagoya, Japan, ¹¹Nagoya Univ Grad Sch Med, Nagoya, Japan, ¹²Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic, ¹³Institute of Rheumatology, Prague, Czech Republic, ¹⁴University of Otago, Christchurch, New Zealand, ¹⁵University of Auckland, Auckland, New Zealand, ¹⁶Jikei Univ Sch Med, Tokyo, Japan, ¹⁷Ryougoku East Gate Clin, Tokyo, Japan, ¹⁸Kyoto Industr Health Assoc, Kyoto, Japan, ¹⁹Tokyo Univ Pharmacy Life Sci, Tokyo, Japan, ²⁰Biochemistry Dept, PO Box 56, University of Otago, Dunedin, New Zealand, ²¹National Defense Med College, Saitama, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: gout, GWAS, hyperuricemia, meta-analysis and polymorphism

Session Information

Date: Sunday, November 5, 2017

Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: We performed a genome-wide association study (GWAS) of gout and its subtypes to identify novel gout loci including those that are subtype-specific.

Methods: Putative causal association signals from a GWAS of 945 cases and 1,213 controls were replicated with 1396 clinically-ascertained gout cases and 1,268 controls of Japanese males by using a custom chip of 1,961 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. Although NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting its indirect association with urate handling. Localization analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron, as well as the proximal nephron, in urate handling in humans. Clinically-defined male gout cases 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). Further findings after this GWAS will be presented at the meeting. We also revealed by a fine mapping that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the CUX2 locus, which was detected by the previous gout GWAS. Further results of a replication study with Japanese for loci detected by a previous gout GWAS with Chinese population will be also discussed at the meeting.

Conclusion: 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 and hyperuricemia.

Disclosure: H. Matsuo, None; A. Nakayama, None; H. Nakaoka, None; K. Yamamoto, None; M. Sakiyama, None; A. Shaukat, None; Y. Toyoda, None; Y. Okada, None; Y. Kamatani, None; M. Nakatochi, None; T. Nakamura, None; T. Takada, None; H. Nakashima, None; S. Shimizu, None; M. Kawaguchi, None; A. Hishida, None; K. Wakai, None; B. Stiburkova, None; K. Pavelka, None; L. K. Stamp, Amgen, 8; N. Dalbeth, Takeda, AstraZeneca, Abbvie, 9; T. Hosoya, None; M. Kubo, None; H. Ooyama, None; T. Shimizu, None; K. Ichida, None; T. R. Merriman, Ardea Biosciences, 2; N. Shinomiya, None.

To cite this abstract in AMA style:

Matsuo H, Nakayama A, Nakaoka H, Yamamoto K, Sakiyama M, Shaukat A, Toyoda Y, Okada Y, Kamatani Y, Nakatochi M, Nakamura T, Takada T, Nakashima H, Shimizu S, Kawaguchi M, Hishida A, Wakai K, Stiburkova B, Pavelka K, Stamp LK, Dalbeth N, Hosoya T, Kubo M, Ooyama H, Shimizu T, Ichida K, Merriman TR, Shinomiya N. Genome-Wide Association Study of Clinically-Ascertained Gout and Subtypes Identifies Multiple Susceptibility Loci Including Transporter Genes [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genome-wide-association-study-of-clinically-ascertained-gout-and-subtypes-identifies-multiple-susceptibility-loci-including-transporter-genes/. Accessed .

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