OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

• Klíčová slova
• Japanese, genome-wide association study (GWAS), gout/hyperuricaemia, selection pressure analysis, subtype specific locus,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• celogenomová asociační studie * MeSH
• dna (nemoc) epidemiologie   genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci etnologie   MeSH
• genetické lokusy MeSH
• genotyp MeSH
• hodnocení rizik MeSH
• incidence MeSH
• lidé MeSH
• mitochondriální aldehyddehydrogenasa genetika   MeSH
• nádorové proteiny genetika   MeSH
• prognóza MeSH
• referenční hodnoty MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Japonsko MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• ALDH2 protein, human MeSH Prohlížeč
• mitochondriální aldehyddehydrogenasa MeSH
• nádorové proteiny MeSH

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). 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). 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 versus 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 level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

• Klíčová slova
• asymptomatic hyperuricemia, genome-wide association study, gout, individually-tailored preemptive medicine, uric acid,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• asymptomatické nemoci MeSH
• celogenomová asociační studie MeSH
• dna (nemoc) krev   genetika   MeSH
• dospělí MeSH
• genetické lokusy genetika   MeSH
• genotypizační techniky MeSH
• hyperurikemie genetika   MeSH
• kontaktiny genetika   MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• mitochondriální aldehyddehydrogenasa genetika   MeSH
• nádorové proteiny genetika   MeSH
• proteiny usnadňující transport glukosy genetika   MeSH
• rizikové faktory MeSH
• zinkové prsty genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• ALDH2 protein, human MeSH Prohlížeč
• CNTN5 protein, human MeSH Prohlížeč
• kontaktiny MeSH
• kyselina močová MeSH
• mikro RNA MeSH
• MIRN302A microRNA, human MeSH Prohlížeč
• mitochondriální aldehyddehydrogenasa MeSH
• nádorové proteiny MeSH
• proteiny usnadňující transport glukosy MeSH
• SLC2A9 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• Arthritis, Gene Polymorphism, Gout,
• MeSH
• Asijci genetika   MeSH
• běloši genetika   MeSH
• celogenomová asociační studie * MeSH
• dna (nemoc) klasifikace   genetika   MeSH
• DNA vazebné proteiny MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genetické lokusy MeSH
• genotyp MeSH
• histony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kotransportní proteiny pro sodík a fosfát - typ I genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• přenašeče organických aniontů genetika   MeSH
• proteiny buněčného cyklu MeSH
• proteiny přenášející kationty genetika   MeSH
• proteiny přenášející organické kationty genetika   MeSH
• proteiny genetika   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• validační studie MeSH
• Geografické názvy
• Japonsko MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• histony MeSH
• kotransportní proteiny pro sodík a fosfát - typ I MeSH
• NIPAL1 protein, human MeSH Prohlížeč
• přenašeče organických aniontů MeSH
• proteiny buněčného cyklu MeSH
• proteiny přenášející kationty MeSH
• proteiny přenášející organické kationty MeSH
• proteiny MeSH
• SHLD2 protein, human MeSH Prohlížeč
• SLC17A1 protein, human MeSH Prohlížeč
• SLC22A12 protein, human MeSH Prohlížeč