RESUMO
Despite progress in understanding of the genetic basis of gout, the precise factors affecting differences in gout susceptibility among different gout subtypes remain unclear. Using clinically diagnosed gout patients, we conducted a genome-wide meta-analysis of two distinct gout subtypes: the renal overload type and the renal underexcretion type. We provide genetic evidence at a genome-wide level of significance that supports a positive association between ABCG2 dysfunction and acquisition of the renal overload type.
Assuntos
Predisposição Genética para Doença , Gota , Gota/genética , Humanos , Japão , Rim , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Gout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02-1.68] for rs10821905 of A1CF, P = 6.49 × 10-3, OR with 95% CI: 1.29 [1.07-1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10-4, OR with 95% CI: 1.39 [1.17-1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10-5, OR with 95% CI 1.32 [1.15-1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.
Assuntos
Predisposição Genética para Doença/genética , Genética Populacional , Estudo de Associação Genômica Ampla , Gota/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Povo Asiático/genética , Feminino , Humanos , MasculinoRESUMO
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.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aldeído-Desidrogenase Mitocondrial/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Gota/genética , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Loci Gênicos , Genótipo , Gota/epidemiologia , Humanos , Incidência , Japão , Masculino , Fenótipo , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Contactinas/genética , Gota/genética , Hiperuricemia/genética , MicroRNAs/genética , Dedos de Zinco/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Assintomáticas , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fatores de Risco , Ácido Úrico/sangueRESUMO
Human leukocyte antigen phenotypes and radiographic course were studied in 70 Japanese patients (90 hips) who had Charnley low friction arthroplasty. Of the 28 hips diagnosed as radiographically loose less than 15 years after surgery, seven hips (25.0%) were in patients who had a positive human leukocyte antigen A31(19). Of the 62 hips that were radiographically stable more than 15 years, two hips (3.2%) were in patients who had a positive human leukocyte antigen A31(19). Of the nine hips in patients who were positive to human leukocyte antigen A31(19), seven hips were diagnosed as radiographically loose (loosening rate was 77.8%) 15 years after surgery. On the other hand, of the 81 hips in the patients who were negative to human leukocyte antigen A31(19), only 21 hips were diagnosed as radiographically loose (loosening rate was 25.9%) 15 years after surgery. These data suggest that individual immune response to implant materials, linked to human leukocyte antigen, may participate in the process of aseptic loosening in Charnley low friction arthroplasty.
