Research Article: TIM family gene polymorphism and susceptibility to rheumatoid arthritis: Systematic review and meta-analysis

Date Published: February 7, 2019

Publisher: Public Library of Science

Author(s): Bahman Razi, Samira Esmaeili Reykandeh, Shahab Alizadeh, AliAkbar Amirzargar, Amene Saghazadeh, Nima Rezaei, Miguel Marcos.


TIM-family proteins are expressed on different immune cells such as dendritic cells, macrophages, type 1 and 2 T helper (Th) cells. Therefore, they have the ability to contribute to the various intracellular signals and immune responses, importantly the regulation of Th1 and Th17 cell differentiation, which plays a remarked role in fight against inflammatory and autoimmune diseases. Association of TIM family gene polymorphisms with rheumatoid arthritis (RA) has been frequently investigated. The findings however are not entirely consistent. Therefore, we carried out the present meta-analysis to examine the association between RA and the following TIM family gene polymorphisms: rs41297579, rs1036199, rs10515746, and rs7700944.

A systematic search of Scopus, PubMed, and Web of Science databases was conducted through December 2018. Combined odds ratios (OR) with their corresponding 95% confidence intervals (CI) were calculated under different possible genetic models.

A total of eight case-control studies were included in the present meta-analysis. The results demonstrated significant association of RA with TIM-3 rs1036199 polymorphism under dominant (OR, 1.93, 95% CI, 1.43–2.61) and allelic models (OR, 1.74, 95% CI, 1.31–2.30). None of the other examined polymorphisms indicated significant association with RA.

The present meta-analysis revealed that the TIM-3 rs1036199 polymorphism might confer susceptibility to RA. Further studies are required to reassert our findings.

Partial Text

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive inflammation of the synovial membrane of the joint capsule and tendons (synovitis). Clinical manifestations range from chronic pain, loss of joint function, and deformity, to disability and systemic complications [1, 2]. RA usually develops between 40 and 50 years of age. Like most autoimmune diseases, RA is more common in women than men (3:1 ratio) [3]. Its prevalence increases with age and varies across different regions of the world [4, 5]. Despite clear clinical manifestations of the disease, the exact etiology and pathogenesis of RA remain obscure. Generally genetic and environmental factors have been well-associated with autoimmune disorders. Particularly, the role of genetic factors in the pathogenesis of RA has been confirmed by family and twin studies. Accordingly, the heritability of RA is estimated to be about 60% [6, 7]. Furthermore, genome-wide association studies (GWAS) have identified more than 100 genetic loci related to RA [8–12]. Of note, genome-side meta-analysis by Okada and colleagues recently introduced nine new loci including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2 as genetic risk factors for RA in Japanese population [12].

The present meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement (S1 File) and meta-analysis on genetic association studies checklist (S2 File) [30].

Xie et al. 2017 [46] emphasized the association of TIM family gene polymorphisms, especially variants of the TIM1, with susceptibility to asthma through a meta-analysis study. Though some studies have investigated the association of RA with these polymorphisms, the associations remain unclear because the results are not conclusive. Therefore, we conducted this meta-analysis of data driven from eight studies that examined the relationship between RA and TIM family gene polymorphisms (rs41297579, rs1036199, rs10515746, rs7700944). Accordingly, the TIM-3 rs1036199 polymorphism was demonstrated to affect susceptibility to RA.

In sum, the current meta-analysis provided evidence that TIM-3 G>T (+4259) gene polymorphism might increase the risk of RA. The analyses, however, failed to found significant association between RA and other polymorphisms of TIM family genes. Further studies with larger sample sizes across different race/ethnic groups are warranted to validate the findings.




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