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. 2024 Dec 18:17:4803-4816.
doi: 10.2147/DMSO.S480366. eCollection 2024.

IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation

Jinju Li  1 , Hao Yang  2 , Tingting Wang  1 , Nuobing Ruan  1 , Yixuan Lin  3 , Zhaohui Fang  3   4
Affiliations

IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation

Jinju Li et al. Diabetes Metab Syndr Obes. .

Abstract

Objective: Studies have demonstrated a link between chronic inflammatory responses and diabetic microangiopathy, which include diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. However, it remains unclear whether there is a causal association between circulating inflammatory cytokines and the development of diabetic microvascular complications. This study aimed to investigate whether altered genetically predicted concentrations of circulating inflammatory cytokines were associated with the development of diabetic microvascular complications using two-sample Mendelian randomization (MR) analysis and clinical validation.

Methods: Pooled data on diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and 91 circulating inflammatory cytokines were obtained from publicly available databases. The analysis was conducted mainly using the inverse variance weighting (IVW) method and the results were assessed based on the odds ratio (OR) and 95% confidence interval (CI). In addition, the stability and reliability of the results were verified using the leave-one-out method, heterogeneity tests, and horizontal pleiotropy. Finally, ELISA and RT-qPCR were utilized to assess the expression of relevant inflammatory cytokines associated with diabetic microvascular complications.

Results: Mendelian randomization analysis identified a total of 9 circulating inflammatory cytokines that exhibit causal associations with the diabetic microangiopathy, with IL-20RA being a common risk factor for all three conditions. Clinical studies have found elevated plasma IL-20RA concentrations in patients with diabetic peripheral neuropathy, and RT-qPCR testing of peripheral blood mononuclear cells revealed significantly higher IL-20RA mRNA expression in patients with diabetic peripheral neuropathy as compared to normal individuals.

Conclusion: This study highlights the potential role of specific inflammatory cytokines in the development of diabetic microangiopathy (diabetic nephropathy, diabetic retinopathy and diabetic neuropathy). Additionally, IL-20RA emerges as a potential common risk factor for three diabetic microvascular complications. These findings may provide novel insights into early prevention and new therapeutic strategies for diabetic microvascular complications.

Keywords: IL-20RA; Mendelian randomisation; circulating inflammatory cytokines; diabetic microangiopathy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow chart of Mendelian randomization study.
Figure 2
Figure 2
Causal effect of circulating inflammatory cytokines on diabetic microangiopathy: (A) Circular plots of the causal relationship between circulating inflammatory cytokines and diabetic microangiopathy. (B) Forest plot of the causal relationship between circulating inflammatory cytokines and diabetic microangiopathy.
Figure 3
Figure 3
Scatter plot of the effect of circulating inflammatory cytokines on diabetic microangiopathy. (A) CCL-7 and diabetic nephropathy (B) CSF-1 and diabetic nephropathy (C) IFNG and diabetic nephropathy (D) IL-1A and diabetic nephropathy (E) IL-20RA and diabetic nephropathy (F) IL-24 and diabetic nephropathy (G) IL-1A and diabetic retinopathy (H) IL-20RA and diabetic retinopathy (I) SLAM and diabetic retinopathy (J) STAMBP and diabetic retinopathy (K) IL-20RA and diabetic neuropathy (L) IL-24 and diabetic neuropathy (M) SLAM and diabetic neuropathy (N) TNFSF14 and diabetic neuropathy.
Figure 4
Figure 4
“Leave-one-out” diagram of the effects of 91 circulating inflammatory cytokines on diabetic microangiopathy. (A) CCL-7 and diabetic nephropathy (B) CSF-1 and diabetic nephropathy (C) IFNG and diabetic nephropathy (D) IL-1A and diabetic nephropathy (E) IL-20RA and diabetic nephropathy (F) IL-24 and diabetic nephropathy (G) IL-1A and diabetic retinopathy (H) IL-20RA and diabetic retinopathy (I) SLAM and diabetic retinopathy (J) STAMBP and diabetic retinopathy (K) IL-20RA and diabetic neuropathy (L) IL-24 and diabetic neuropathy (M) SLAM and diabetic neuropathy (N) TNFSF14 and diabetic neuropathy.
Figure 5
Figure 5
Comparison of IL-20RA concentration and relative expression levels between the two groups: (A) Comparison of plasma IL-20RA levels between patients in the DPN group and the normal group (B). Relative expression of IL-20RA mRNA in PBMCs of DPN group and the normal group *** represents P<0.001 **** represents P<0.0001.
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References

    1. Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 [published correction appears in Diabetes Res Clin Pract2023 Oct;204:110945]. Diabetes Res Clin Pract. 2022;183:109119. doi:10.1016/j.diabres.2021.109119 - DOI - PMC - PubMed
    1. Sabanayagam C, Chee ML, Banu R, et al. Association of diabetic retinopathy and diabetic kidney disease with all-cause and cardiovascular mortality in a multiethnic Asian population. JAMA Network Open. 2019;2(3):e191540. doi:10.1001/jamanetworkopen.2019.1540 - DOI - PMC - PubMed
    1. An J, Nichols GA, Qian L, et al. Prevalence and incidence of microvascular and macrovascular complications over 15 years among patients with incident type 2 diabetes. BMJ Open Diabetes Res Care. 2021;9(1):e001847. doi:10.1136/bmjdrc-2020-001847 - DOI - PMC - PubMed
    1. Fu H, Liu S, Bastacky SI, et al. Diabetic kidney diseases revisited: a new perspective for a new era. Mol Metab. 2019;30:250–263. doi:10.1016/j.molmet.2019.10.005 - DOI - PMC - PubMed
    1. Lin KY, Hsih WH, Lin YB, et al. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. J Diabetes Investig. 2021;12(8):1322–1325. doi:10.1111/jdi.13480 - DOI - PMC - PubMed

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