OBJECTIVES: MicroRNAs (miRNAs) are short single-stranded RNAs that play a role in the post-transcriptional regulation of gene expression. Their deregulation can be associated with various diseases, such as cancer, neurodegenerative, and immune-related diseases. The aim of our study was to compare miRNA levels in plasma that could potentially influence the progression of hyperuricemia to gout, since the mechanism of progression is still unclear. METHODS: Total RNA, including miRNA, was isolated from the plasma of 45 patients with asymptomatic hyperuricemia, 131 patients with primary gout (including 16 patients having a gout attack), and 130 normouricemic controls. The expression of 18 selected miRNAs (cel-miR-39 and cel-miR-54 as spike-in controls, hsa-miR-16-5p and hsa-miR-25-3p as endogenous controls, hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30a-3p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-133a-3p, hsa-miR-142-3p, hsa-miR-143-3p, hsa-miR-146a-5p, hsa-miR-155-5p, hsa-miR-222-3p, hsa-miR-223-3p, hsa-miR-488-3p and hsa-miR-920) was measured using qPCR. RESULTS: We found that hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30c-5p, hsa-miR-142-3p, and hsa-miR-223-3p were significantly upregulated (p < 0.001) in the plasma of hyperuricemia and gout patients compared to normouricemic individuals. As part of the follow-up of our previous study, we found a negative correlation between hsa-miR-17-5p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-142-3p, and hsa-miR-223-3p with plasma levels of chemokine MCP-1. Additionally, we found a positive correlation between CRP and plasma levels of hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-142-3p, hsa-miR-146a-5p, hsa-miR-155-5p, hsa-miR-222-3p, and hsa-miR-223-3p. Five of those miRNAs (hsa-miR-126-3p, hsa-miR-142-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-222-3p) also had a positive correlation with serum creatinine and therefore a negative correlation with eGFR. CONCLUSION: Five miRNAs were significantly upregulated in the plasma of patients with hyperuricemia and gout (and those during a gout attack) compared to normouricemic controls. We also found a correlation between the plasma levels of several miRNA and plasma levels of MCP-1, CRP, serum creatinine, and eGFR.

• Keywords
• Acute gouty arthritis, Gout, Hyperuricemia, Uric acid, miRNA,
• MeSH
• Circulating MicroRNA * MeSH
• Gout * genetics   MeSH
• Hyperuricemia * genetics   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Humans MeSH
• MicroRNAs * genetics   MeSH
• Gene Expression Regulation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Circulating MicroRNA * MeSH
• MicroRNAs * MeSH

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K-a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type-has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397-405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations-c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

• Keywords
• ABCG2 genotype, Roma, SUA-lowering therapy, clinico-genetic analysis, ethnic specificity, genetic variations, precision medicine, rare variant, serum uric acid, urate transporter,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   metabolism   MeSH
• Child MeSH
• Gout complications   genetics   MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• HEK293 Cells MeSH
• Hyperuricemia blood   complications   genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Uric Acid blood   MeSH
• Humans MeSH
• Mutation MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Organic Anion Transporters genetics   metabolism   MeSH
• Pedigree MeSH
• Transfection MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ABCG2 protein, human MeSH Browser
• Uric Acid MeSH
• Neoplasm Proteins MeSH
• Organic Anion Transporters MeSH
• urate transporter MeSH Browser

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.

• Keywords
• Japanese, genome-wide association study (GWAS), gout/hyperuricaemia, selection pressure analysis, subtype specific locus,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   MeSH
• Genome-Wide Association Study * MeSH
• Gout epidemiology   genetics   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease ethnology   MeSH
• Genetic Loci MeSH
• Genotype MeSH
• Risk Assessment MeSH
• Incidence MeSH
• Humans MeSH
• Aldehyde Dehydrogenase, Mitochondrial genetics   MeSH
• Neoplasm Proteins genetics   MeSH
• Prognosis MeSH
• Reference Values MeSH
• Case-Control Studies MeSH
• Severity of Illness Index MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Japan MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ABCG2 protein, human MeSH Browser
• ALDH2 protein, human MeSH Browser
• Aldehyde Dehydrogenase, Mitochondrial MeSH
• Neoplasm Proteins MeSH