In this study, we found that the IL-6 rs12700386 polymorphism led to an increased risk of OA, especially among drinkers, smokers, those older than 55 years old, and with a BMI ≥25 kg/m2. The interactions between the IL-6 rs12700386 polymorphism and smoking and/or drinking combined to lead to a further increase in risk for knee OA. Certain genotypes of the rs12700386 polymorphism were associated with increased IL-6 expression. We found that IL-6 levels were significantly higher in OA patients with the CC genotype compared to the GG genotype. However, the impact of rs12700386 on OA patients with regards to their clinical parameters remains unknown.
OA is characterized by the destruction of cartilage, remodeling of subchondral bone, and synovial membrane inflammation, all of which actively affect disease progression [13]. As shown in previous studies, tibiofemoral cartilage injury progression can be affected by reactive or inflammatory synovium [14]. Proinflammatory cytokines such as IL-6 and TNF, can dramatically mediate metabolic disorders as well as enhance catabolism of OA joint tissue [13]. The synovial fluid and serum of OA patients has been shown to have significantly increased IL-6 levels [15]. A clinical trial involving OA patients showed that the risk of cartilage loss increases when IL-6 and CRP have high baseline levels [16]. Increase in circulating IL-6 level and high BMI could lead to radiographic keen risk of OA [17]. In mice, IL-6 deficiency has been found to lead to a reduction in both the number of arthritic cells in the knee and the collagen-induced arthritis response [18]. However, the exact mechanism of how IL-6 affects OA is of considerable debate.
IL-6 gene polymorphisms may change gene function and expression and regulate susceptibility to osteoarthritis [11, 12]. We carried out this case-control study to explore the influence of IL-6 gene polymorphism on the risk of knee OA. Although Singh et al. found that there was no association between IL-6 rs12700386 and OA risk, they showed that IL-6 plasma levels were significantly related to specific rs12700386 genotypes [11]. However, our findings showed that rs12700386 increased susceptibility to OA. This inconsistency between studies may be attributed to 4 main factors. First, people living in different environments have different diets and lifestyles. Second, our data indicated that there is between interplay between IL-6 gene rs12700386 polymorphism and some exposure factors. Third, different genotyping approaches, as well as inclusion criteria, were used in each study. Finally, OA exhibits clinical heterogeneity which can lead to the variation of OA classification between studies.
Based on stratified analyses, smokers, drinkers, subjects older than 55, and with a BMI ≥25 kg/m2 had an increased risk of knee OA. The cross-over analysis was thus used to estimate the combined effects of IL-6 gene polymorphism and smoking and drinking on knee OA risk. Data indicated that smokers carrying the GG genotype and drinkers carrying the GA genotype were more prone to OA. This also suggests that gene-environment interactions could influence the occurrence of OA. The combined effects of rs12700386 polymorphisms and smoking and/or drinking enhanced susceptibility to OA. We also evaluated the associations between IL-6 gene polymorphisms and clinical characteristics of OA, however, no evidence of an association between rs12700386 and the clinical parameters of OA patients was found. To explore underlying mechanisms, qRT-PCR analysis showed that rs12700386 contributed to an increase IL-6 gene levels. We also found that IL-6 levels were significantly higher in CC genotype compared to GG genotype carriers in OA patients. Singh et al. demonstrated that genotypes of IL-6 rs12700386 was associated with increased levels of IL-6 in OA patients which was consistent with our study [11]. The possible mechanism for this may be that the change of guanine (G) to cytosine (C) at − 2954 position (−2954G/C; rs12700386) positively activate IL-6 transcriptional efficacy and hence, increases the IL-6 serum levels. Our study has shown that the IL-6 gene polymorphism can affect IL-6 gene expression and serum levels leading to an increase in the risk of knee OA.
This study does have some shortcomings. 1) only a moderate sample size was used, incapable of completely exploring how IL-6 gene rs12700386 polymorphism affected the knee OA susceptibility. 2) there may also have been some selection bias related to the ethnic groups as the participants were limited to the Chinese population. 3) only 1 polymorphism of the IL-6 gene was examined; it could not completely cover the gene. Further studies with haplotype analysis for IL-6 promoter polymorphisms are needed to profound our study. 4) relevant experiments were not carried out to fully elucidate underlying mechanisms. In further study, relevant experiments, such as transfection experiments, are need to demonstrate increased IL-6 promoter activity in the presence of the minor allele.