Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.

• MeSH
• dna (nemoc) * genetika   MeSH
• hyperurikemie * genetika   MeSH
• kotransportní proteiny pro sodík a fosfát - typ I * genetika   MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• přenašeče organických aniontů nezávislé na sodíku * genetika   MeSH
• přenašeče organických aniontů * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kotransportní proteiny pro sodík a fosfát - typ I * MeSH
• kyselina močová MeSH
• přenašeče organických aniontů nezávislé na sodíku * MeSH
• přenašeče organických aniontů * MeSH
• SLC17A1 protein, human MeSH Prohlížeč
• SLC22A11 protein, human MeSH Prohlížeč
• SLC22A13 protein, human MeSH Prohlížeč
• urate transporter 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