Investigating the Causal Association Between Polymyalgia Rheumatica and Hypothyroidism Using Mendelian Randomization Analysis.
INTRODUCTION To perform a two-sample Mendelian randomization (MR) analysis to explore the potential causal relationship between polymyalgia rheumatica (PMR) and hypothyroidism. METHODS Genome-wide association study (GWAS) data for PMR and hypothyroidism were obtained from publicly available databases. The inverse variance weighted (IVW) method was primarily used to evaluate the potential causal effect of PMR-related traits on the risk of hypothyroidism. To assess the robustness of the findings, additional methods, including the weighted median (WME), MR-Egger (ME), simple mode (SM), and weighted mode (WM), were employed. Sensitivity analyses were performed using the MR-PRESSO method and Cochran's Q test to detect potential heterogeneity and horizontal pleiotropy. Furthermore, a reverse MR analysis was performed to investigate the possibility of reverse causality. RESULTS IVW analysis demonstrated a significant causal relationship between PMR and hypothyroidism (OR=1.373, 95%CI:1.287-1.465, P=5.84×10⁻²²). In contrast, ME produced a non-significant result (OR=0.880, 95%CI:0.602-1.286, P=0.577). WME supported IVW findings (OR=1.373, 95%CI:1.280-1.480, P=8.97×10⁻¹⁸), as did WM (OR=1.410, 95%CI:1.243-1.599, P=0.013) and the SM (OR=1.398, 95%CI:1.240-1.575, P=0.012). Collectively, these findings provide evidence supporting a causal effect of PMR on the risk of hypothyroidism. Reverse MR analysis using the IVW method also indicated a significant causal association (OR=1.195, 95%CI:1.135-1.258, P=9.35×10-12). However, both ME regression and IVW heterogeneity tests showed evidence of heterogeneity (P=3.16×10⁻³⁸; P=4.11×10⁻³⁸). The ME analysis revealed no evidence of horizontal pleiotropy (P=0.615). DISCUSSION A study suggested that hypothyroidism-induced myopathic changes may mimic or exacerbate PMR symptoms, potentially leading to misdiagnosis or overtreatment with corticosteroids. Importantly, recurrence of PMR symptoms has been observed after thyroid hormone replacement, even in the presence of normalized thyroid function. These findings underscore a potential bidirectional relationship between PMR and hypothyroidism. In addition, some researchers held that HLA-B8 and DR3 may be a significant indicator to assess the association between these diseases; however, some observations suggest that it may not serve as a specific risk marker for PMR or its complications. CONCLUSION PMR is closely associated with the development of hypothyroidism; the risk of hypothyroidism increases as PMR progresses; on the other hand, advancing hypothyroidism may also raise the likelihood of developing PMR.