TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells.
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 < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-γ expression in CD4+ T cells.
Department of Orthopedics, Qianfoshan Hospital, Shandong University, 16766 Jing Shi Road, Jinan, Shandong, 250014, China, shufenglisd@126.com.
Shufeng
S
Li
Yanjun
Y
Ren
Dayong
D
Peng
Zhen
Z
Yuan
Shiying
S
Shan
Huaqiang
H
Sun
Xinfeng
X
Yan
Hong
H
Xiao
Guang
G
Li
Haihan
H
Song
D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*
C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D007371:Interferon-gamma