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.
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 April 7, 2020.
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