Background
Knee osteoarthritis (OA) is a common joint disease which is characterized by degeneration of articular cartilage and subsequent subchondral bone changes [
1]. The incidence of knee OA is high, with an estimated 14 million symptomatic patients in the USA [
2]. Therefore, it is an enormous burden on the national economy and healthcare system. Knee OA is a combined consequence of environmental and genetic factors, while genetic factors account for nearly 50% of the risk of knee OA development [
3]. Though the underlying mechanisms remain unknown, many studies have demonstrated that the occurrence of osteoarthritis is related to genetic factors, including interleukin-17 family [
4‐
7].
Interleukin-17 (IL-17) families include six members (A, B, C, D, E, F), and they play active roles in autoimmune diseases and inflammatory diseases [
8,
9]. IL-17A is a member of IL-17 families and is a pro-inflammatory cytokine associated with many inflammatory diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, and systemic lupus erythematosus [
10]. Similarly, IL-17F earned increasing attention due to its great comparability of IL-17A. Previous studies reveal that IL-17 is expressed in synovial tissues, and could contribute to cartilage degeneration, the main cause of knee OA, by inducing the release of chemokines by chondrocytes [
11]. Although knee OA is considered a non-inflammatory condition earlier, with further researches on its physiopathology, it is generally believed that immune cell infiltration and cytokine secretion are a feature of knee OA [
12]. The expression of IL-17A and IL-17F has turned out to be affected by single nucleotide polymorphisms (SNPs). These polymorphisms have allele-specific effects on the regulation of IL-17 gene transcription and are associated with the development and/or progression of some common diseases [
13]. Thus, we hypothesized that IL-17A(rs2275913) and IL-17F(rs763780) gene polymorphisms are associated with knee OA risk.
Up to now, several studies have investigated the relationships of IL-17A(rs2275913) and IL-17F(rs763780) polymorphism with knee OA risk in different countries and draw different conclusions [
14‐
19]. Jiang [
14] and Han [
15] found that the IL-17A(rs2275913) polymorphism was involved in high risk of KOA while the IL-17F(rs763780) was not. Bai [
16] and Eftedal [
19] found that IL-17A/F gene polymorphisms all related to the high-risk knee OA occurrence. Bafrani [
18] found that IL-17A(rs2275913) gene may be a protective factor against knee osteoarthritis while the IL-17F(rs763780) gene may be a risk factor for knee osteoarthritis. Vrgoc [
17] revealed that neither IL-17A nor IL-17F were related to the knee OA. Therefore, we conducted a meta-analysis to overcome the limitations of individual studies and to search for relevance in their findings. The purpose of this study was to evaluate whether the IL-17A(rs2275913) and IL-17F(rs763780) polymorphisms are associated with the risk of knee OA.
Discussion
To our knowledge, this is the first meta-analysis to investigate the associations between IL-17A(rs2275913) and IL-17F(rs763780) gene SNPs and knee OA risk. The most important finding was that polymorphisms of IL-17A(rs2275913) and IL-17F(rs763780) gene associate with the risk of knee osteoarthritis in different ethnics. This finding proves our assumption that polymorphisms of IL-17A/F are associated with the occurrence of knee osteoarthritis and is a risk factor for the knee OA.
The definite mechanisms of the knee OA remain unknown, but many studies have shown that genetic factors are considered to be strong determinants with them, and the occurrence of knee osteoarthritis is related to inflammatory and cytokines [
22‐
24]. Recent studies have suggested that knee OA might be considered a chronic inflammatory disorder, elevated levels of IL-1, IL-6, IL-17,TNF-α, and other acute-phase proteins that are found in patients with cartilage degradation [
25]. A kind of conventional viewpoint is that inflammatory mechanism plays a crucial role in the pathogenesis and evolution of cartilage degeneration and expression of inflammatory reaction [
26‐
28]. IL-17 is one of the most important regulators of innate and adaptive immune responses, and it is expressed in synovial tissues, and could contribute to cartilage degeneration and synovial infiltration in joint by inducing the release of chemokines by chondrocytes [
29,
30]. Furthermore, studies in animal models suggest that IL-17 knock-out mice contribute to more severe RA than wild-type animals [
31]. We have reasons to believe that IL-17 may contribute to the development of knee OA. Therefore, we conducted this meta-analysis to provide more confident evidence.
In our study, 6 eligible studies, including 2134 knee OA patients and 2306 controls for gene rs2275913 and 2134 knee OA patients and 2426 controls s for gene rs763780, were identified and analyzed. We demonstrated the association between IL-17A(rs2275913) and IL-17F(rs763780) and the knee OA risk by a meta-analysis to obtain a convincing conclusion. Our research suggests that IL-17A(rs2275913) and IL-17F(rs763780) gene polymorphisms are a risk factor for knee osteoarthritis (p < 0.05). Different alleles play different roles in the occurrence of knee OA. As for IL-17A(rs2275913), it is believed that allele A can promote the high expression of IL-17A, which may be a risk factor for the occurrence of osteoarthritis. In our study, the A allele in case groups was indeed higher than that in the control groups. And we found the OR was higher than 1 in allele model and recessive model, which means A allele can be a mutant gene influence the development of knee OA. The genotype of IL-17F(rs763780) was similar to IL-17 A(rs2275913). The OR of allele model (C vs T) and recessive model (CC vs TT + TC) was higher than 1, while the OR with 95% CI of dominant model (TC + CC vs TT) was 0.97–1.80. This means CC genotype can increase the risk of knee OA, and we can conclude that the C allele was a mutant gene and recessively expressed in human.
Subgroup analysis revealed that the results were altered between Asian and Caucasian groups. The heterogeneity was decreased significantly in recessive model (I2 = 0%, p = 0.932) and allele model (I2 = 29.8%, p = 0.240) of IL-17A(rs2275913) and all three models (I2 = 0%, p > 0.05) of IL-17 A(rs2275913) in the Caucasian group, we believe that ethnic was the main source of heterogeneity. Heterogeneity mainly exists in the Asian group, which may be related to the complex ethnic composition of the Asian population. Subgroup analysis stratified by ethnicity demonstrated that A allele increased the risk of knee OA in Asian. While in Caucasian, no association was found between IL-17 A(rs2275913) and the risk of knee OA. The results seem intriguing that there is an association in the overall population but without positive result in subgroups. It could be probably statistically insufficient when the majority of cases of the study were originated from Asian. And one other possibility may relate to the different expression patterns of IL-17A and IL-17F in non-homogeneous ethnic populations.
Despite the fact that the result shows a relevance between IL-17A(rs2275913) and IL-17F(rs763780) and risk of knee OA, there are still some facts we cannot ignore. Firstly, the occurrence of knee osteoarthritis is a comprehensive result of a variety of factors and genes, and a single gene may have little impact on this result. Secondly, there may be some unidentified alleles affecting the expression of IL-17, and the gene loci (rs2275913, rs763780) may not be the only factor affecting the expression of IL-17 in the population. Third, regardless of the fact that IL-17A and IL-17F can mediate cartilage degeneration, it may not be a direct determinant of osteoarthritis. Many cytokines of IL-17 family are involved in the inflammatory reaction. The destruction of articular cartilage is the common result of many cytokines. IL-17 cannot directly reflect the effect of inflammatory reaction changes on osteoarthritis. Subgroup analysis in our study shows no statistical difference in different ethnic groups; gene expression may still have a certain influence, in spite of considering the limited articles involved.
There are still some limitations in our paper. Firstly, our several genetic models have great heterogeneity when combining OR values, which may affect the accuracy of the article. For this reason, we used random effect model to combine OR values and conduct subgroup analysis to reduce the impact of heterogeneity. In this way, results of heterogeneity test are acceptable in some subgroups. Secondly, although six papers have been included in the study, the data scale is still small, and further experiments with larger samples in different ethnic populations are needed to verify this conclusion. Thirdly, since the data is not completely available, the potential confounding factors (such as age, gender) were not adjusted in this study. Last, though there was no obvious publication bias revealed by Begg’s test, the selection bias could not be completely removed because only studies published in English were included.
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