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.
- MeSH
- Asijci genetika MeSH
- běloši genetika MeSH
- celogenomová asociační studie * MeSH
- dna (nemoc) klasifikace genetika 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 přenášející kationty genetika MeSH
- proteiny přenášející organické kationty genetika MeSH
- proteiny genetika MeSH
- původní obyvatelé Havajských a ostatních tichomořských ostrovů 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
