Nan Chu

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10−13, BCAS3), 9p24.2 (rs12236871, P=1.48 × 10−10, RFX3) and 11p15.5 (rs179785, P=1.28 × 10−8, KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

IL-8 –251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population

Objectives: Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate NALP3 and mediate interleukin (IL)-1β generation from its inactive pro-form, resulting in cellular activation and an IL-8-mediated neutrophil influx into the joint. IL-8 and IL-12 are important chemokines related to the initiation and amplification of acute and chronic inflammatory processes. In this study, we investigated whether the IL-8 –251T/A and IL-12 1188A/C polymorphisms are associated with susceptibility to gout in a Chinese Han male population. Methods: Overall, 387 patients with gout and 576 controls were included in this study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). An association analysis was carried out using the χ2 test. A genotype–phenotype analysis was also conducted. Results: The T allele of IL-8 –251 was associated with risk of gout [p = 0.031 (odds ratio (OR) 1.229, 95% confidence interval (CI) 1.019–1.483]. There was a clear link between the IL-12 1188 AA and AC genotypic and A allelic frequencies between gout cases and controls (p < 0.001, df = 2 by genotype; p < 0.001, OR 1.404, 95% CI 1.165–1.691 by allele). Conclusions: Our results suggest that the IL-8 –251T/A and IL-12B 1188A/C polymorphisms may be relevant host susceptibility factors for the development of gout.

Polymorphisms in the Presumptive Promoter Region of the SLC2A9 Gene Are Associated with Gout in a Chinese Male Population

Background Glucose transporter 9 (GLUT9) is a high-capacity/low-affinity urate transporter. To date, several recent genome-wide association studies (GWAS) and follow-up studies have identified genetic variants of SLC2A9 associated with urate concentrations and susceptibility to gout. We therefore investigated associations between gout and polymorphisms and haplotypes in the presumptive promoter region of GLUT9 in Chinese males. Methodology/Principal Findings The approximately 2000 bp presumptive promoter region upstream of the start site of exon 1 of GLUT9 was sequenced and subjected to genetic analysis. A genotype-phenotype correlation was performed and polymorphisms-induced changes in transcription factor binding sites were predicted. Of 21 SNPs identified in GLUT9, five had not been previously reported. Two of the SNPs (rs13124007 and rs6850166) were associated with susceptibility to gout (p = 0.009 and p = 0.042, respectively). The C allele of rs13124007 appeared to be the risk allele for predisposition to gout (p = 0.006, OR 1.709 [95% CI 1.162–2.514]). For rs6850166, an increased risk of gout was associated with the A allele (p = 0.029, OR 1.645 [95% CI 1.050–2.577]). After Bonferroni correction, there was statistically difference in rs13124007 allele frequencies between gout cases and controls (P = 0.042). Haplotype analyses showed that haplotype GG was a protective haplotype (p = 0.0053) and haplotype CA was associated with increased risk of gout (p = 0.0326). Genotype-phenotype analysis among gout patients revealed an association of rs13124007 with serum triglycerides levels (P = 0.001). The C to G substitution in polymorphism rs13124007 resulted in a loss of a binding site for transcription factor interferon regulatory factor 1 (IRF-1). Conclusions/Significance Polymorphisms rs13124007 and rs6850166 are associated with susceptibility to gout in Chinese males.

Positive Correlation Between Beta-3-Adrenergic Receptor (ADRB3) Gene and Gout in a Chinese Male Population

Objective. The common polymorphism rs4994 [c. T387C, p. Trp64Arg (W64R)] of the lipolysis regulator beta-3-adrenergic receptor (ADRB3) was identified as a marker in the pathogenesis of hyperuricemia. As gout is characterized by elevated serum concentrations of uric acid, we investigated ADRB3 as a potential candidate for gout. Methods. This was a prospective case-control study in a group of 421 male patients with gout and 312 gout-free male controls to genotype the single-nucleotide polymorphism rs4994 of ADRB3 gene. Results. Our results showed that the C allele carrier confers a significantly higher risk for development of gout [chi-square = 4.91, df = 1, p = 0.027, OR 1.95 (adjusted by age, total cholesterol level, and body mass index), 95% CI 1.22–3.13 by dominant mode]. There was significantly higher uric acid level in carriers of the Arg64/Arg64 genotype in controls compared to non-carriers (480.5 mmol/l vs 315.0 mmol/l, respectively). Conclusion. ADRB3 rs4994 polymorphism is a potential candidate for the pathogenesis of gout in a male Chinese population.

Associations between interleukin and interleukin receptor gene polymorphisms and risk of gout

Gout is a self-limiting, auto-inflammatory arthritis induced by the deposition of monosodium urate crystals in the synovial fluid and periarticular tissues. The aim of this study was to investigate the associations between genetic variants in the interleukin (IL) and interleukin receptor (ILR) genes IL-33, IL-1RL1, IL-23R, and signal transducer and activator of transcription 4 (STAT4) and susceptibility to gout in Chinese Han male individuals. The genetic distributions of rs3939286 in IL-33, rs13015714 in IL-1RL1, rs10889677 in IL-23R, and rs7574865 in STAT4 were detected in 1100 men with gout and 1227 ethnically matched controls, using Taqman allelic discrimination real-time polymerase chain reaction (PCR). Differences in these polymorphisms between the groups were investigated using χ2 tests. The genotype-phenotype relationship among gout patients was tested by analysis of variance. There was a significant difference in genotypic frequencies of IL-23R rs10889677 between gout patients and controls (χ2 = 81.386, P < 0.001). However, there were no significant differences in distributions of the other polymorphisms between the groups. Our results revealed that the rs10889677 variant in IL-23R may be involved in the development of gout in Chinese Han male individuals. However, further studies in other ethnic groups are needed to confirm these results.

The hURAT1 rs559946 polymorphism and the incidence of gout in Han Chinese men

Objectives: Our previous study identified rs559946, a human urate transporter 1 (hURAT1) single nucleotide polymorphism (SNP), as being significantly associated with risk of primary hyperuricaemia (HUA) in a Han Chinese population. In the current study we aimed to identify the genetic effects of rs559946 on gout susceptibility in Han Chinese men. Method: A total of 335 patients with gout and 376 healthy controls were recruited for a case–control association study. To examine the functional effect of rs559946, we performed luciferase reporter assays and an electrophoretic mobility shift assay (EMSA). Results: rs559946 was found to be significantly associated with gout susceptibility (p = 0.004), with T-allele carriers showing a decreased risk of gout [odds ratio (OR) 0.70, 95% confidence interval (CI) 0.55–0.89]. Multiple linear regression analysis identified a significant association between rs559946 genotypes and tophi. Luciferase reporter assays show increased transcriptional activity of the hURAT1 promoter with the C allele of rs559946. EMSA detected binding of nuclear proteins to both the T and C alleles, although increased binding was observed with the T allele. Cold competition assays suggest that rs559946 may bind within a glucocorticoid receptor (GR) binding motif. Conclusions: Our study suggests that the rs559946 polymorphism is associated with increased HUA risk and may also contribute to gout development in Han Chinese men. The T to C substitution within rs559946 increased the transcriptional activity, and potentially increases gout susceptibility.

Lack of association of -607 C/A and -137 G/C polymorphisms in interleukin 18 gene with susceptibility to gout disease in Chinese Han male population

To identify association of IL18-607 C/A and -137 G/C polymorphism with susceptibility to gout in Chinese Han male population, We evaluate the genetic contribution of the IL18-607 C/A and -137 G/C polymorphism in 202 gout male patients and 493 gout-free control of Chinese Han population by allele-specific polymerase chain reaction assay. Our results reveal no significant association between the polymorphisms -607C/A and -137G/C in IL18 with gout. Our study might suggest that -607 C/A and -137 G/C polymorphisms in the promoter of IL18 are not associated with susceptibility to gout and thus do not play a major role in the development of gout in the Chinese Han male population.

Polymorphisms -1082 G/A and -819 C/T in the interleukin-10 gene are not associated with gout susceptibility in the Chinese Han male population.

BACKGROUND Gout is caused by monosodium urate crystal-induced inflammation of the joints and periarticular tissues. Interleukin 10 (IL-10) is an important immunoregulatory cytokine, levels of which can be influenced by functional single-nucleotide polymorphisms in the promoter. OBJECTIVE To investigate the association of -1082 G/A and -819 C/T polymorphisms in the IL-10 promoter with gout susceptibility in the Chinese Han male population. METHODS A case-control study was performed in 302 patients and 284 controls. Genotyping of IL-10 -1082 G/A and -819 C/T polymorphisms was performed by DNA sequencing techniques. An association analysis was analyzed by the χ(2) test. RESULTS No significant differences were found in -819T/C and -1082 A/G genotypic and allelic frequencies between gout cases and controls (for -819T/C, χ(2)=0.212, df=1, p=0.645 by genotype; χ(2)=0.079, df=1, p=0.779 by allele; for -1082 A/G, χ(2)=2.116, df=1, p=0.146 by genotype; χ(2)=1.854, df=1, p=0.173 by allele). CONCLUSIONS IL-10 -1082 G/A and -819 C/T polymorphisms may not be associated with susceptibility to gout and thus do not play a major role in the development of gout in the Chinese Han male population.