Hypertension, Dyslipidemia, and Adhesive Capsulitis: A Bidirectional Two-Sample Mendelian Randomization Study of the...

Whether hypertension and dyslipidemia are risk factors for adhesive capsulitis (AC) remains controversial. Many observational studies have reported conflicting results. However, observational studies are susceptible to confounding and reverse causation, limiting the ability to establish causality. Therefore, a robust method is needed to clarify these relationships.

We first conducted a hospital-based case-control study that included 200 AC patients and 200 controls. Multivariate logistic regression was used to examine the associations of hypertension and dyslipidemia with AC after adjusting for potential confounders. To address the inherent limitations of observational studies, we then performed a two-sample Mendelian randomization (MR) analysis. We obtained datasets related to essential hypertension, dyslipidemia, and AC from a public genome-wide association study (GWAS) database. Inverse variance weighted (IVW) served as the primary analysis method. Sensitivity analyses included MR-PRESSO to detect outliers and pleiotropy and Cochran's Q test (combined with MR-Egger and IVW) to assess heterogeneity. The robustness of the findings was evaluated using a leave-one-out analysis. Finally, a bidirectional MR analysis was conducted by swapping the exposures and outcomes to test for reverse causality.

In the clinical case-control study, multivariate logistic regression revealed that age (OR: per year: 1.061, 95% CI: 1.034-1.089, p < 0.001) and diabetes (OR: 2.153, 95% CI: 1.271-3.646, p = 0.004) were independently associated with AC, whereas neither hypertension (OR: 1.406, 95% CI: 0.870-2.274, p = 0.164) nor dyslipidemia (OR: 1.760, 95% CI: 0.912-3.395, p = 0.092) showed a significant association with AC. Consistent with the observational findings, MR analysis detected no causal effect of hypertension or dyslipidemia on AC. However, reverse MR analysis identified a significant negative causal effect of AC on high-density lipoprotein (HDL) cholesterol (OR: 0.989, 95% CI: 0.982-0.997, p = 0.008) and a positive causal effect of AC on the apolipoprotein B/A1 ratio (OR: 1.018, 95% CI: 1.001-1.034, p = 0.033).

Our MR analysis revealed a negative causal effect from AC to HDL cholesterol and a positive causal effect from AC to the apolipoprotein B/A1 ratio. These findings provide evidence for the temporal sequence and reverse causal relationship between AC and dyslipidemia. The convergent results from both clinical and genetic analyses support the robustness of this causal relationship and highlight AC as a potential driver of lipid abnormalities. Therefore, these findings underscore the need for further experimental and mechanistic studies to elucidate the underlying biological mechanisms.