SLC2A9 gene polymorphism in Korean patients with gouty arthritis

Abstract

Gout is an inflammatory disease with accumulation of monosodium urate (MSU) crystals in joints. The prevalence of gout is continuously increasing due to Westernized diet and life style in Korea.The predisposing factors of gout are male gender, old age, alcohol consumption, renal insufficiency, and use of diuretics. There were studies on the association of genetic predisposition such as single nucleotide polymorphism (SNP) of SLC2A9 gene, which is involved in reabsorption of uric acid in renal tubule and gout. However, most of these studies on genetic association were performed on Caucasian populations, although genetic variations exist among different ethnic groups. Thus, an independent study is required to identify inter-racial genetic variations and gene polymorphisms unique to Korean gout patients. We set out to elucidate genetic polymorphisms of SLC2A9 gene related to gout pathogenesis, and identify those findings to various clinical indices related to gout.Three hundred thirty three gout patients and 459 healthy controls were included in this study. Minor allele frequency exceeding over 5 percent was selected as tagging SNP through sequencing of exon, promoter, and intron near exon in SLC2A9 gene in 12 gout patients and in 12 controls. Two SNPs within SLC2A9 (rs6820230, rs3775950), which showed high correlation to gout in pilot study including 96 gout patients and 48 controls, were selected and genotyped using TaqMan SNP genotyping assays. Additionally, rs16890979, which had demonstrated significant correlation to gout and serum uric acid level among Caucasians in previous studies, and rs1014290, which had been reported to be associated to gout in Koreans, Japanese, and other Han Chinese, were selected to be analyzed. An association analysis was carried out using the Chi-squared test or Fisher''s exact test. Genotype-phenotype analyses were conducted using Chi-squared test, Fisher’s exact test or Kruskal-wallis analysis. The major allele of rs6820230 is C, minor allele is T, the major allele of rs3775950 is A, minor allele is G, the major allele of rs1014290 is T, minor allele is C, and the major allele of rs16890979 is C, minor allele is T. The T allele of rs6820230 was associated with increased risk of gout (P = 0.0003, OR 1.977, 95% CI 1.363, 2.867), and the risk of gout was elevated 1.9 fold in subject with genotype TT than in subject with genotype CT, and in subject with CT than in subject with genotype CC, respectively. The G allele of rs3775950 increased the risk of gout (P < 0.0001, OR 2.133, 95% CI 1.457, 3.122), and the risk of gout was 2.2 fold elevated in subject with genotype GG than in subject with genotype AG, and in subject with genotype AG than in subject with genotype AA, respectively. In rs1014290, T allele was found to be associated with the development of gout (P < 0.0001, OR 1.564, 95% CI 1.269, 1.928), and the risk of gout was 1.58 fold elevated in subject with genotype TT than in subject with genotype CT, and in subject with CT than in subject with CC, respectively. There was no significant association between blood pressure, body mass index, the level of cholesterol, triglyceride, urea nitrogen, creatinine, fasting glucose, and each SNPs. Stratification of the phenotypes by genotypes did not demonstrate any different results. The association between rs16890979 and serum uric acid concentration was statistically significant only in male gout patients. Serum concentrations of uric acid were 9.39 ± 1.60 mg/dl, 7.5 mg/dl, and 11.80 ± 0.85 mg/dl in subjects with genotype CC, CT, and TT, respectively. The association between rs3775950 and age of diagnosis was statistically significant only in female gout patients. There were no significant genotype-related differences among severe gout patients with tophi or X-ray abnormality, and gout patients who had experienced allopurinol hypersensitivity.Our results suggest that genetic variants within SLC2A9, such as rs6820230 (C/T), rs3775950 (A/G), and rs1014290 (T/C) polymorphisms have significant effects on the development of gout in Korean population. And these results demonstrate that there is an inter-racial genetic difference affecting the pathogenesis of gout.