TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells
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TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells Shufeng Li,1,6 Yanjun Ren,1 Dayong Peng,1 Zhen Yuan,1 Shiying Shan,1 Huaqiang Sun,1 Xinfeng Yan,1,6 Hong Xiao,2 Guang Li,3,5,6 and Haihan Song4,5,6
Abstract—Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-γ) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, −574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction–restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95 % confidence interval [CI] 1.32–5.11, P< 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR =2.58, 95 % CI 1.29–4.82, P = 0.003). The TIM-3 −574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-γ expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-γ in CD4+ T cells compared to wild-type GG genotype (P 0.05 and P>0.05, respectively), whereas the BMI of cases were significantly higher than the BMI of healthy controls (P0.05
95 (36.3) 167 (63.7) 24.8 ± 4.2
105 (34.9) 196 (65.1) 23.2 ± 4.9
>0.05
51 (19.5) 211 (80.5)
53 (17.6) 248 (82.4)
52 (19.8) 128 (48.9) 49 (18.7) 33 (12.6)
0.05
subjects were Kellgren–Lawrence grade III, and 33 (12.6 %) subjects were Kellgren–Lawrence grade IV (Table 1). TIM-3 Single-Nucleotide Polymorphism and Susceptibility to Osteoarthritis Distribution of the TIM-3 +4259T/G and −574G/T SNPs in OA patients and healthy donors are summarized in Table 2. As for the TIM-3 −574G/T polymorphism, the percentage of −547GT genotype was 6.5 % in OA cases and 5.0 % in healthy donors. The −574 genotypes did not present a significant difference between patients and controls (Table 2). The number of patients and controls with −574T allele were 17 and 15, respectively. No significant difference was observed (Table 2). As for the TIM-3 +4259T/G SNP, the percentage of +4259TG genotype was significantly higher in OA cases compared to healthy controls (OR=2.67, 95 % CI 1.32–5.11, P0.05 and P>0.05, Fig. 1a, b). Also, patients with different TIM-3 −574G/T genotypes revealed similar levels of IFN-γ in CD4+ T cells (P>0.05 and P>0.05, Fig. 1c, d). For the TIM-3 +4259T/G polymorphism, we examined IFN-γ in CD4+ T cells from 20 healthy controls
Li, Ren, Peng, Yuan, Shan, Sun, Yan, Xiao, Li, and Song Table 2. TIM-3 SNPs in OA Patients and Controls
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