TRAF2 and TRAF5, members of the TRAF family, could activate downstream intracellular signaling cascades through its cell surface receptors. Meanwhile, as non-HLA region genes, TRAF2 and TRAF5 are highly polymorphic. Therefore, it is necessary to explore the association between TRAF2 and TRAF5 gene polymorphisms and the susceptibility to ankylosing spondylitis.
This study showed that, rs3750511 of TRAF2 gene may be the susceptibility site of AS in Chinese Han female population, which further indicates that TNF signaling may increase AS susceptibility, especially in female population. For the difference in gender susceptibility, the most likely cause was usually considered as sex hormones, which were important regulators of the immune response process . To investigate whether TRAF2 and TRAF5 gene polymorphisms are not only associated with the occurrence of disease, but also with disease development and disease activity, we conducted the stratified analysis based on disease activity indicators. The results indicated that the allele frequencies of rs10781522 and the genotype frequencies of rs3750511 were statistically significant between groups of BASDAI < 4 and BASDAI ≥ 4. The above results indicated that rs10781522 and rs3750511 polymorphism may be associated with disease activity in AS. TRAF2, a member of the TRAF family, could activate the C-JNK and IKK pathways, which in turn induce the expression of genes involved in inflammation, immune response, cell proliferation, cell differentiation, and inhibition of death receptor-induced apoptosis . Meanwhile, some studies reported TRAF2 gene expression was related to the level of TNF-α, which may explain the association between the SNPs of TRAF2 gene and the disease activity of AS.
Numerous studies showed that there were common genetic pathways and immune mechanisms between ankylosing spondylitis and inflammatory bowel disease and rheumatoid arthritis. And it was found that rs7514863 SNP on TRAF5 gene was associated with rheumatoid arthritis . However, in this study, we found no significant differences in the distribution of genotype frequency, allele frequency and inheritance model of rs7514863 between AS patients and healthy controls. The reason for this difference may be due to ethnic differences, the same genetic locus of the same disease may also have different results depending on ethnicity. In addition, although the genetic pathway of ankylosing spondylitis has many similarities with rheumatoid arthritis, it is likely that this gene locus is not in the common pathway of the two diseases, resulting in the difference in results. Similarly, Xiang Q et al. also suggested that rs12569232 of TRAF5 was significantly associated with uveitis , while our study showed that TRAF5 rs12569232 was not significantly associated with susceptibility to AS. The reason for this inconsistency may be that the immune mechanism of TRAF5 in the two diseases is different, or it may be that the sample size of our study is insufficient, leading to different results.
Routine statistical analysis using the MDR method found that the interaction between TRAF2 and TRAF5 genes was significantly associated with ankylosing spondylitis. The optimal gene-gene interaction model was identified as three locus model, namely TRAF2 (rs10781522, rs17250673) and TRAF5 (rs4951523). Based on these findings, we speculated that because ankylosing spondylitis is a complex autoimmune disease, individual genetic mutation may only have a small edge effect on its pathogenesis, and it is difficult to detect . In other words, certain components in the development of AS, such as TRAF2 and TRAF5, may act synergistically in ways that we are still unclear. TRAF2 and TRAF5 are both members of the TRAF family of genes, and they work together on many pathways. For example, the NF-κB signaling pathway can still be activated after single knockout of TRAF2 or TRAF5, but it can be deactivated after double knockout of TRAF2 and TRAF5 . Therefore, it is necessary to study the relationship between the interaction between TRAF2 and TRAF5 and ankylosing spondylitis.
Additionally, rs3750511 polymorphism may be associated with sleep quality in the dominant model. The reasons for the correlation are as follows: Firstly, rs3750511 is related to disease activity, and higher disease activity may affect the sleep quality of patients. Secondly, P value is 0.036, which is greater than 0.05 after correction. Positive correlation may also be statistically correlated with accidental factors. Thirdly, there are some missing values of environmental factors investigated in this study, and false positive results may also occur. In the partially absence of the data of environmental factors, we persisted in the analysis because the results of the analysis of the association between environment and genes may could provide clues for further research.
There are some limitations in this study. Firstly, the sample size of this study, especially in female subgroup, is moderate, the results should be interpreted with caution, and independent, multi-center, large-scale studies are needed to validate our results. Secondly, no correlation analysis between gene polymorphism and drugs was conducted to explore whether gene polymorphism affects patients' susceptibility to drugs, which remains to be further explored.