In this paper, we explored the genetic association between adipokines and the development of RA, finding that per one unit increase in natural log-transformed resistin levels could be causally associated with 28% increased risk of RA occurrence. Whereas, little evidence supported causal associations of genetically predicted adiponectin, leptin, chemerin or RBP4 levels with the RA risk. Our analysis results indicate that regulating the circulating resistin to appropriate levels may lower the incidence of RA, which could be useful in future clinical practice. To the best of our knowledge, this is the first MR study to evaluate the potential causal association between circulating adipokine levels and risk of RA.
A large number of observational epidemiological studies have been undertaken to investigate the role of adipokines in the occurrence and progression of RA. Two recent meta-analyses of case-control studies demonstrated that circulating adiponectin levels could be significantly higher in the RA patients than those in the health controls [30, 31]. However, it was also reported separately that adiponectin levels were not related to RA activity [30, 32]. Meanwhile, the findings from meta-analyses consistently indicated that patients with RA may have higher circulating leptin levels compared with the control group [33–35]. Two of these studies further established a correlation between leptin levels and RA activity [34, 35]. Several case-control studies have also suggested associations of chemerin and RBP4 concentrations with RA [36, 37]. However, our MR results suggested that genetically predicted levels of adiponectin, leptin, chemerin or RBP4 were not causally associated with risk of RA. The inconsistency between our MR analysis and the previous observational studies may be attributed to the following reasons. Firstly, the previously published results are mostly based on retrospective case-control studies with a small sample size, which are particularly prone to recall and selection biases. This thereby leads to an even weaker causal argument. Secondly, residual confounding (e.g., the adipokines may be correlated with other factors that impact on RA risk) and reverse causation (e.g., RA may have resulted in high or low circulating adipokine levels) may further limit the ability of causal inference in the traditional observational studies. Thirdly, MR studies provide causal estimates of the impact of lifetime adipokines levels on RA, which might diverge from the short-term effects as assessed in traditional observational studies.
For resistin, our MR results were broadly compatible with the findings of the previous meta-analysis outcomes [38]. Several biological mechanisms have been proposed to interpret the potential effect of resistin on the pathogenesis of RA. It is widely recognized that RA is a persistent inflammatory diease, which is related to several inflammatory cytokines [39]. Šenolt et al. reported that resistin was expressed in different inflammatory cells of RA synovial tissue, including macrophages (CD68), B lymphocytes (CD20) and plasma cells (CD138) [40]. Those authors speculated that resistin was involved in the activation of these cells as a signaling molecule in RA. Subsequently, a case-control study found a positive association of serum resistin with C-reactive protein levels in RA patients, further supporting the potential pro-inflammatory effects of resistin in this disease. Futhermore, synovial liquid resistin levels have been claimed to be significantly associated with rheumatoid factor and anti-citrullinated protein antibody [41], both of which are markers of RA. Cellular analysis suggested that resistin down-regulates the expression of microRNA 206 via protein kinase C delta (PKC-δ/AMPK) signaling pathway to promote endothelial progenitor cell (EPC) migration and RA angiogenesis. In addition, resistin induced the vascular endothelial growth factor (VEGF) expression, which was also associated with EPC migration and tube formation [42]. Therefore, resistin plays an important role in the pathogenesis of RA and may being a potential target for RA intervention.
Our investigation has some potential limitations. Firstly, it is known that genetic variants only explain a relatively small proportion of variation in adipokines, which may lead to inadequate power to detect causal associations in studies with small sample sizes [43]. Secondly, pleiotropy is considered to be the most challenging limitation of MR analysis. Even though none of the performed MR analyses showed an indication of pleiotropy, we were unable to completely rule out the possibility that pleiotropy had affected the results. Thirdly, our MR analysis were conducted using participants of European ancestry. While restricting the investigation to racially homogeneous populations reduces the population stratification bias, our findings may not be applicable to other populations for different genetic backgrounds. Finally, for the use of summary-level data, we were unable to perform subgroup analyses to address study-specific factors, e.g., age, sex and other RA risk faciors.
In conclusion, the present MR study indicates that genetically predicted circulating resistin levels are positively associated with risk of RA. This can be beneficial for the development of clinical as well as public health strategies. Nevertheless, we encourage futher prospective studies and MR analyses with more genetic instruments and longitudinal studies, which follow up RA patients over time monitoring the risk factors and outcome, to be conducted to confirm the results.