免疫球蛋白G N-糖基化模式与糖尿病并发症之间的因果关联：两样本孟德尔随机化研究

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

作者信息

Zhang Xiaohuan

机构信息

Department of Special Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, and People's Hospital of Henan University, Zhengzhou, Henan, China.

出版信息

Diabetol Metab Syndr. 2025 Jul 18;17(1):284. doi: 10.1186/s13098-025-01858-7.

DOI:10.1186/s13098-025-01858-7

PMID:40682148

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12275434/

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.

摘要

背景

为阐明免疫球蛋白G（IgG）N-糖基化模式（IGP）与糖尿病并发症之间的相关性，这些并发症包括糖尿病肾病（DN）、糖尿病视网膜病变（DR）和糖尿病黄斑病变（DM）。我们进行了一项两样本孟德尔随机化（MR）研究。

方法

我们从医学研究委员会人类遗传学单位和芬兰基因联盟获得了与77种IGP和糖尿病并发症相关的全基因组关联研究（GWAS）汇总统计数据。在我们的两样本MR研究中，与IGP相关的基因变异被用于估计相关性。采用逆方差加权（IVW）方法作为主要分析方法。实施了各种补充方法，包括MR-Egger、加权中位数（WM）和加权模式，以检测因果关系。敏感性分析包括MR-PRESSO、MR-Egger、 Cochr an's Q和留一法，用于验证结果的稳健性。

结果

经过MR-PRESSO异常值校正和严格的错误发现率（FDR）校正后，确定了显著的因果关联：较高水平的IGP48与糖尿病黄斑病变（DM）风险增加密切相关（OR：1.21，95%CI：1.09-1.35，P = 0.001，FDR = 0.004）。此外，还观察到其他几个名义上的关联（P < 0.05），这些关联在FDR校正后不成立，但提示了未来的研究方向。其中包括IGP18（OR：0.86，P = 0.033）和IGP35（OR：0.90，P = 0.015）对DM的保护关联，以及IGP23（OR：1.19，P = 0.028）和IGP28（OR：1.17，P = 0.038）的风险关联。对于糖尿病视网膜病变（DR），发现IGP35存在名义上的保护关联（OR：0.94，P = 0.026），IGP48存在风险关联（OR：1.07，P = 0.042）。敏感性分析未检测到显著的水平多效性，结果稳定。