In this study, we found that IL-6 rs12700386 polymorphism led to an increased OA risk, especially among drinkers, smokers, and those ≥55 years old or with BMI ≥25 kg/m2 . The interactions between IL-6 rs12700386 polymorphism and smoking and drinking contributed to an increased risk for knee OA. In addition, genotypes of rs12700386 polymorphism were associated with increased IL-6 gene levels. Nevertheless, the impact of rs12700386 on OA patients regarding the clinical parameters remains unknown.
OA is characterized by destruction of cartilage, remodeling of subchondral bone and synovial membrane inflammation, which actively affects the disease progression . As demonstrated by studies, tibiofemoral cartilage injury progression can be clearly affected by reactive or inflammatory synovium . Proinflammatory cytokines like IL-6, TNF, can dramatically mediate metabolic disorders as well as enhance the catabolism regarding OA joint tissue . The synovial fluid and serum of OA patients also presented significantly increased IL-6 and sIL-6R levels . On the basis of a clinical trial on OA patients, if IL-6 and CRP held a high baseline level, the cartilage loss risk would increase . Increase in circulating IL-6 level and high BMI could lead to radiographic keen OA risk . Furthermore, IL-6 deficiency in mice has been found to lead to reduced knee arthritis cell number as well as collagen-induced arthritis response . However, how IL-6 exactly affect the OA is of considerable debate.
IL-6 gene polymorphisms may change the function and expression of gene and regulate the susceptibility to osteoporosis. Thus, we performed the case-control study for exploring the impact exerted by IL-6 gene polymorphism on the knee OA risk. Recently, as found by Monica Singh et al, despite the irrelevance between IL-6 rs12700386 and OA risk, IL-6 plasma level was significant related to the genotypes of rs12700386 . However, our finding showed that rs12700386 increased the susceptibility of OA. This inconsistency may be attributed to 4 reasons. First, people living in different environments have different eating habits and living styles. Second, our data indicated the interplay between IL-6 gene rs12700386 polymorphism and some exposure factors, which are evidently diverse. Third, different genotyping approaches as well as inclusion criteria possibly come into different results. Fourth, clinical heterogeneity exhibited by OA is possibly resulted from the conflicting results due to the variation of OA malignancy degree between studies.
Furthermore, based on stratified analyses, knee OA risk increased in smokers, drinkers, and subjects ≥55 years old or with BMI ≥25 kg/m2. Thus, the cross-over analysis was used to estimate the combined effects of IL-6 gene polymorphism and smoking and drinking on knee OA risk. As expected, the combined effects of rs12700386 polymorphism and smoking and drinking conferred susceptibility to OA. In addition, we evaluated the associations between IL-6 gene polymorphism and clinical characteristic of OA. However, no evidence was found to prove that rs12700386 is associated with the clinical parameters of OA patients. To explore the underlying mechanisms, the qRT-PCR of IL-6 gene showed the rs12700386 contributed to increase IL-6 gene levels. Thus, our study indicated that the IL-6 gene polymorphism could affect the IL-6 gene level and the knee OA risk.
There are also some shortcomings in the study. 1) it had a moderate sample size, incapable of accurately exploring how IL-6 gene rs12700386 polymorphism affected the knee OA susceptibility. 2) there may have been a selection bias related to the ethnic groups as the participants were limited to Chinese population. 3) only 1 polymorphism of the IL-6 gene was examined; it could not completely cover the gene. 4) relevant experiments were not carried out for figuring out underlying mechanisms.