Dataset Information

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

ABSTRACT: 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 (p meta =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.

SUBMITTER: Nakayama A

PROVIDER: S-EPMC5530361 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

Nakayama Akiyoshi A Nakaoka Hirofumi H Yamamoto Ken K Sakiyama Masayuki M Shaukat Amara A Toyoda Yu Y Okada Yukinori Y Kamatani Yoichiro Y Nakamura Takahiro T Takada Tappei T Inoue Katsuhisa K Yasujima Tomoya T Yuasa Hiroaki H Shirahama Yuko Y Nakashima Hiroshi H Shimizu Seiko S Higashino Toshihide T Kawamura Yusuke Y Ogata Hiraku H Kawaguchi Makoto M Ohkawa Yasuyuki Y Danjoh Inaho I Tokumasu Atsumi A Ooyama Keiko K Ito Toshimitsu T Kondo Takaaki T Wakai Kenji K Stiburkova Blanka B Pavelka Karel K Stamp Lisa K LK Dalbeth Nicola N Sakurai Yutaka Y Suzuki Hiroshi H Hosoyamada Makoto M Fujimori Shin S Yokoo Takashi T Hosoya Tatsuo T Inoue Ituro I Takahashi Atsushi A Kubo Michiaki M Ooyama Hiroshi H Shimizu Toru T Ichida Kimiyoshi K Shinomiya Nariyoshi N Merriman Tony R TR Matsuo Hirotaka H

Annals of the rheumatic diseases 20161129 5

<h4>Objective</h4>A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.<h4>Methods</h4>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 a ...[more]

PMID: 27899376

Similar Datasets

Project description:IntroductionThere is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets.MethodsA total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata.ResultsA haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039).ConclusionsOur analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.

Dataset Information

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

Publications

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets