As a common chronic condition, KOA is the main cause of pain in the knee joint that affects routine activities such as walking long distances, climbing stairs, sports activities, and even daily household activities, thereby seriously affecting the patients’ quality of life. A variety of plausible factors have been confirmed to be involved in this disease. Through years of genome-wide association studies, genetic factors have been considered an important determinant of OA (19). Therefore, exploring the genetic pathogenesis of OA can help in early diagnosis and improved prevention and treatment of the disease.
It is well-known that degeneration of cartilage is a crucial pathobiological process in the development and progression of KOA. ECM is mainly composed of collagen, the aggregating proteoglycan aggrecan, and many other macromolecules, while cartilage is composed of a large amount of ECM and a relatively small number of chondrocytes embedded in it (41). In OA, the degradation of ECM macromolecules surpasses their synthesis, eventually leading to total or partial cartilage erosion (42). As a critical ECM-degrading enzyme, ADAMTS-5 can cleave the Glu373–Ala374 bond in the IGD of aggrecan (20), thereby mediating the cartilage aggrecan degradation, which is thought to be a significant event in early-stage OA (24).
The ADAMTS-5 gene is located on chromosome 21q21.3 and regulates the synthesis of the ADAMTS-5 protein (24, 43). Several studies have focused on the association of ADAMTS-5 with the susceptibility to OA; however, their conclusions were inconsistent. Rodriguez-Lopez et al. explored the association between six tag SNPs (rs3746836, rs162495, rs162488, rs9984329, rs233896, and rs233601) and two nonsynonymous SNPs (nsSNP) (rs226794 and rs2830585) of ADAMTS-5 and OA in different parts of the body (e.g., hip OA, knee OA, and hand OA) on samples obtained from four European Caucasian collections. The results of their study did not reveal any significant effects of ADAMTS-5 SNPs on the susceptibility to OA (31). Nevertheless, as that study is the first and the largest study for the association of OA with ADAMTS5 SNPs, it is worth referring to despite the fact that no positive results were found. Canbek et al. conducted a case–control study in a Turkish population, and their results also showed that the ADAMTS-5 SNPs (rs226794 and rs2830585) variants may not contribute to the susceptibility to KOA (33). In China, Gu et al. conducted a community-based case–control study and reported that the T allele carrier in rs2830585 could be a protective factor against OA, especially cervical OA (32). In contrast, Zhou et al. found that the T allele carrier in rs2830585 was associated with a significantly increased risk of KOA (34).
In the previous studies on the association between ADAMTS-5 SNPs and susceptibility to KOA, only a few SNPs have been studied, and the findings have been inconsistent. Thus, the association between ADAMTS-5 polymorphism and OA has not been comprehensively investigated. Therefore, in the present hospital-based case–control study, the associations of 12 tag SNPs (rs226794, rs162497, rs7510287, rs2830585, rs233598, rs2830586, rs151065, rs162496, rs229054, rs162499, rs2249350, rs151058) in the ADAMTS-5 gene with the risk of KOA were investigated in a Chinese Han population.
Our results demonstrated a significant difference in the ADAMTS-5 SNPs between the case and control groups, indicating an association between genetic polymorphism and the susceptibility to KOA. We identified the SNP rs2249350 polymorphic AA genotype of ADAMTS-5 and variant A allele as the protective factors against KOA. In contrast, the variant allele, polymorphic genotypes, and genetic models of other ADAMTS-5 SNPs (rs226794, rs162497, rs7510287, rs2830585, rs233598, rs2830586, rs151065, rs162496, rs229054, rs162499, rs151058) showed no associations with the susceptibility to KOA. We also found that the GA haplotype (rs229054, rs2249350) was associated with a reduced risk of KOA, whereas the GC haplotype (rs229054, rs2249350) was associated with an increased risk of KOA.
Our study showed that rs2249350, but not rs2830585 polymorphisms, were associated with the susceptibility to KOA, which conflicts with the conclusions of previous studies that had reported that rs2830585 was associated with the risk of KOA (34). This discrepancy may be attributed to different sample sizes, ethnicity-dependent effects, and environmental factors. First, the sample size of the case and control groups in this study was much smaller than that in the previous studies. Second, the type of OA, disease severity, and population ethnicity varied among the studies. Other factors may be different BMI, smoking habits, and comorbidities such as diabetes, which may have also contributed to the inconsistent findings. Apart from this, we hypothesize that genetic heterogeneity, different genotyping methods, and random errors may be additional reasons for the different findings between the present and previous studies. Notably, to the best of our knowledge, our study is the first to find a significant association between ADAMTS-5 rs2830585 polymorphism and the susceptibility to KOA in a Chinese Han population.
Due to the crucial role of ADAMTS-5 in cartilage degradation, we hypothesize that the mechanism by which the ADAMTS-5 SNPs affect the susceptibility to KOA may be that the differences in SNPs cause changes in ADAMTS-5 molecular activity or secretion, which in turn could affect the degradation and destruction of cartilage. In a sense, the SNPs in ADAMTS-5 may actually play an important role in molecular biological functions of cartilage metabolism. However, epigenetic aspects such as the effect of SNP on protein expression were not investigated in this study, which should be the focus of future research.
As KOA is a complex disease affected by gene–gene and gene–environmental interactions, a small number of SNP gene mutations is not sufficient to completely represent the genetic susceptibility to the disease, let alone to explain the overall risk of the disease. Therefore, further studies are needed to elucidate the role of other SNPs of ADAMTS-5 and other related genes involved in the pathogenesis of KOA. Meanwhile, the association of gene–gene interactions, gene–environment interactions, and epigenetics with the susceptibility to KOA should also be explored comprehensively.
There may be some limitations to this study, including selection bias, sample size, ethnicity, and single-center study design. First, in terms of selection bias, we assessed only primary KOA, and other factors that are strongly associated with secondary KOA or potential confounders were strictly controlled at the time of the recruitment of the study subjects or were controlled by multivariate statistical analysis. Therefore, we believe that the patients in the case group were accurately selected and that the possibility of selection bias in our sample was very low. Second, compared with other studies, the sample size of the case and control groups in our study was relatively small; we tried our best to ensure that every individual in our study was appropriately selected in order to maximize the accuracy and validity of the sample in the study. Nonetheless, this cannot fully prevent the lack of statistical power of the study to detect subtle differences. Finally, this study only examined the Chinese Han population, and the results of the Chinese Han population may not be generalizable to other ethnic populations. Therefore, additional studies on different populations are necessary.