Evaluation of bi-directional causal association between obstructive sleep apnoea syndrome and diabetic microangiopathy: a Mendelian randomization study

Abstract

Background: The relationship between obstructive sleep apnea syndrome (OSAS) and diabetic microangiopathy remains controversial.

Objective: This study aimed to use bidirectional two-sample Mendelian Randomization (MR) to assess the causal relationship between OSAS and diabetic microangiopathy.

Methods: First, we used the Linkage Disequilibrium Score Regression(LDSC) analysis to assess the genetic correlation. Then, the bidirectional two-sample MR study was conducted in two stages: OSAS and lung function-related indicators (forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)) were investigated as exposures, with diabetic microangiopathy as the outcome in the first stage, and genetic tools were used as proxy variables for OSAS and lung function-related measures in the second step. Genome-wide association study data came from the open GWAS database. We used Inverse-Variance Weighted (IVW), MR-Egger regression, Weighted median, Simple mode, and Weighted mode for effect estimation and pleiotropy testing. We also performed sensitivity analyses to test the robustness of the results. Furthermore, we performed multivariate and mediation MR analyses.

Results: In the LDSC analysis, We found a genetic correlation between OSAS, FVC, FEV 1, and diabetic microangiopathy. In the MR analysis, based on IVW analysis, genetically predicted OSAS was positively correlated with the incidence of diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy (DN). In the subgroup analysis of DR, there was a significant causal relationship between OSAS and background diabetic retinopathy (BDR) and proliferative diabetic retinopathy (PDR). The reverse MR did not show a correlation between the incidence of diabetic microangiopathy and OSAS. Reduced FVC had a potential causal relationship with increased incidence of DR and PDR. Reduced FEV1 had a potential causal relationship with the increased incidence of BDR, PDR, and DKD. Multivariate MR analysis showed that the association between OSAS and diabetic microangiopathy remained significant after adjusting for confounding factors. However, we did not find the significant mediating factors.

Conclusion: Our results suggest that OSAS may be a cause of the development of diabetic microangiopathy, and OSAS may also be associated with a high risk of diabetic microangiopathy, providing a reference for a better understanding of the prevention of diabetic microangiopathy.

Keywords: Mendelian randomization; diabetic microangiopathy; forced expiratory volume in 1 s; forced vital capacity; obstructive sleep apnea syndrome.

Figure 1

The process of Mendel randomization research. FVC, forced vital capacity; FEV1, forced expiratory volume in one second; IV, instrumental variable; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; MR, Mendelian randomization; OSAS, obstructive sleep apnea syndrome; SNP, single nucleotide polymorphism.

Figure 2

Forest plot of OSAS, FVC, and FEV1 associated with the risk of DR, BDR, and PDR. BDR, background diabetic retinopathy; DR, diabetic retinopathy; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; MR, Mendelian randomization; MR-Eggcr, MR-Egger regression analysis; OSAS, obstructive sleep apnea syndrome; PDR, proliferative diabetic retinopathy; SNP, single nucleotide polymorphism.

Figure 3

Forest plot of OSAS, FVC, FEV1 associated with the risk of DKD. DKD, diabetic kidney disease; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; MR, Mendelian randomization; MR-Eggcr, MR-Egger regression analysis; OSAS, obstructive sleep apnea syndrome; SNP, single nucleotide polymorphism.

Figure 4

Forest plot of OSAS, FVC, FEV1 associated with the risk of DN. DN, diabetic neuropathy; MR, Mendelian randomization; MR-Eggcr, MR-Egger regression analysis; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; OSAS, obstructive sleep apnea syndrome; SNP, single nucleotide polymorphism.

Figure 5

Forest plot of DR, BDR, PDR, DKD, DN associated with the risk of OSAS. BDR, background diabetic retinopathy; DKD, diabetic kidney disease; DN, diabetic neuropathy; DR, diabetic retinopathy; MR, Mendelian randomization; MR-Eggcr, MR-Egger regression analysis; PDR, proliferative diabetic retinopathy; OSAS, obstructive sleep apnea syndrome; SNP, single nucleotide polymorphism.