Causal association between immunoglobulin G N-glycosylation patterns and diabetic complications: two-sample mendelian randomization

Abstract

Background: To elucidate the correlation between immunoglobulin G (IgG) N-glycosylation patterns (IGPs) and diabetes complications, including diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic maculopathy (DM). We performed a two-sample Mendelian randomization (MR) study.

Methods: We obtained genome-wide association studies (GWAS) summary statistics related to 77 IGPs and diabetic complications from the MRC Human Genetics Unit and the FinnGen consortium. In our two-sample MR, genetic variants associated with IGPs were used to estimate correlations. The inverse-variance weighted (IVW) method was used as the primary analysis. Various complementary methods, including MR-Egger, weighted median (WM), and weighted mode were implemented to detect the causal relationship. Sensitivity analyses including MR-PRESSO, MR-Egger, Cochran's Q and leave-one-out methods were used to validate the robustness of the results.

Results: After MR-PRESSO outlier correction and a stringent False Discovery Rate (FDR) correction, a significant causal association was identified: higher levels of IGP48 were robustly associated with an increased risk of diabetic maculopathy (DM) (OR: 1.21, 95% CI: 1.09-1.35, P = 0.001, FDR = 0.004). Additionally, several other nominal associations (P < 0.05) were observed that did not withstand FDR correction but suggest areas for future investigation. These included protective associations with DM for IGP18 (OR: 0.86, P = 0.033) and IGP35 (OR: 0.90, P = 0.015), and risk associations for IGP23 (OR: 1.19, P = 0.028) and IGP28 (OR: 1.17, P = 0.038). For diabetic retinopathy (DR), a nominal protective association was found for IGP35 (OR: 0.94, P = 0.026) and a risk association for IGP48 (OR: 1.07, P = 0.042). Sensitivity analyses detected no significant horizontal pleiotropy, and the results were stable.

Conclusion: Our study provides robust genetic evidence identifying IGP48 as a causal risk factor for DM. Other nominal associations with DM and DR require further validation. IGP48 emerges as a promising biomarker and therapeutic target for DM, warranting further research into its underlying mechanisms and clinical utility.

Trial registration: Not applicable.

Keywords: Diabetic complications; Diabetic retinopathy; IgG N-glycosylation; Instrumental variables; Mendelian randomization.

Fig. 1

Overview of Mendelian randomization

Fig. 2

The IVW and forest plot between IGPs and diabetes complications (positive results)