Mendelian Randomization Analysis of NETs-Associated Inflammatory Traits and Type 2 Diabetes and its Complications

Limin Li; Jing Liu; Ronghao Zeng; Nengliang Ouyang; Juan Wang; Qian Dong; Yunxiu Huang; Nan Wang; Weijia Wang

doi:10.3791/71230

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Research Article

Mendelian Randomization Analysis of NETs-Associated Inflammatory Traits and Type 2 Diabetes and its Complications

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DOI:

10.3791/71230

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August 21st, 2026

Limin Li¹ , Jing Liu² , Ronghao Zeng² , Nengliang Ouyang¹ , Juan Wang¹ , Qian Dong¹ , Yunxiu Huang¹ , Nan Wang¹ , Weijia Wang²

¹Department of Laboratory Medicine, Zhongshan People's Hospital, ²Department of Advanced Diagnostic and Clinical Medicine, Zhongshan People's Hospital

Summary

This two-sample MR study identified potential associations of genetically predicted NETs-associated inflammatory traits with T2DM complications. Genetically predicted IL-6 was inversely associated with diabetic CAD, while NETs were associated with renal and peripheral circulatory complications in T2DM. Sensitivity analyses generally supported the stability of these significant associations.

Abstract

Neutrophil extracellular traps (NETs) -associated inflammatory traits play a significant role in type 2 diabetes mellitus (T2DM) and its complications. Notably, IL-6, a key inflammatory cytokine, is intricately linked to the formation of NETs and the pathogenesis of T2DM and its complications. This study aimed to explore the causal association between NETs-associated inflammatory traits and T2DM, as well as its complications, using a Mendelian Randomization (MR) approach. This study utilized a two-sample MR design with data from Genome-Wide Association Studies (GWAS), comprising a large European population-based meta-analysis for T2DM and its complications. The primary method of analysis was the inverse variance weighted (IVW) approach, complemented by MR-Egger regression, weighted median, and weighted mode methods. Sensitivity analyses included MR-Egger, MR-PRESSO, Cochran’s Q, and leave-one-out methods to assess the robustness of the findings. The study indicated that genetically predicted levels of interleukin-6 (IL-6) were inversely associated with diabetic coronary artery disease (CAD) (OR = 0.8997, 95% CI: 0.8257–0.9803, P = 0.0158). Additionally, NETs showed significant associations with T2DM with renal complications (OR=0.97, 95% CI 0.9428–0.998, P = 0.0358) and T2DM with peripheral circulatory complications(OR = 1.0342, 95% CI 1.002–1.0673, P = 0.037). The significant IVW associations showed no evidence of heterogeneity or horizontal pleiotropy. This study suggests that genetically predicted NETs-associated inflammatory traits are associated with specific T2DM complications. Genetically predicted IL-6 was inversely associated with diabetic CAD, whereas NETs were associated with renal and peripheral circulatory complications in T2DM.

Introduction

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and often accompanied by progressive beta-cell dysfunction, has reached epidemic proportions worldwide¹^,². Including cardiovascular disease, renal failure, neuropathy, and retinopathy, these complications of T2DM impose a substantial burden not only on individuals in terms of their health and quality of life but also on healthcare systems worldwide, straining resources and increasing costs, and on economies³^,⁴. Considering the multifaceted nature of T2DM, it necessitates a nuanced exp....