Association Analysis of NLRP3 Inflammation-Related Gene Promotor Methylation as Well as Mediating Effects on T2DM and Vascular Complications in a Southern Han Chinese Population

Abstract

Objective: To explore the association between the methylation levels in the promoter regions of the NLRP3, AIM2, and ASC genes and T2DM and its vascular complications in a Southern Han Chinese population and further analyze their interaction and mediating effects with environmental factors in T2DM.Methods: A case-control study was used to determine the association between population characteristics, the methylation level in the promoter region of the NLRP3, AIM2, and ASC genes and T2DM and vascular complications. A mediating effect among genes-environment-T2DM and the interaction of gene-gene or gene-environment factors was explored.Results: In the logistic regression model with adjusted covariants, healthy people with lower total methylation levels in the AIM2 promoter region exhibited a 2.29-fold [OR: 2.29 (1.28~6.66), P = 0.011] increased risk of developing T2DM compared with higher-methylation individuals. T2DM patients without any vascular complications who had lower methylation levels (<methylation median) in NLRP3 CpG2 and AIM2 total methylation had 6.45 (OR: 6.45, 95% CI: 1.05~39.78, P = 0.011) and 9.48 (OR: 9.48, 95% CI: 1.14~79.00, P = 0.038) times higher risks, respectively, of developing diabetic microvascular complications than T2DM patients with higher methylation. Similar associations were also found between the lower total methylation of the NLRP3 and AIM2 promoter regions and macrovascular complication risk (NLRP3 OR: 36.03, 95% CI: 3.11~417.06, P = 0.004; AIM2 OR: 30.90, 95% CI: 2.59~368.49, P = 0.007). Lower NLRP3 promoter total methylation was related to a 17.78-fold increased risk of micro-macrovascular complications (OR: 17.78, 95% CI: 2.04~155.28, P = 0.009). Lower ASC CpG1 or CpG3 methylation levels had significant partial mediating effects on T2DM vascular complications caused by higher age (ASC CpG1 explained approximately 52.8% or 32.9% of the mediating effect of age on macrovascular or macro-microvascular complications; ASC CpG3 explained approximately 38.9% of the mediating effect of age on macrovascular complications). No gene-gene or gene-environment interaction was identified in T2DM.Conclusion: Lower levels of AIM2 promoter total methylation might increase the risk of T2DM. NLRP3, AIM2, and ASC promoter total methylation or some CpG methylation loss might increase the risk of T2DM vascular complications, which merits further study to support the robustness of these findings.

CBS gene polymorphism and promoter methylation‐mediating effects on the efficacy of folate therapy in patients with hyperhomocysteinemia

“…DNA methylation‐mediating effects were mostly studied with respect to the occurrence and development of cardiovascular and other diseases . The conclusions were similar to the present study in that DNA methylation could play a mediating role in the development of diseases.…”

“…DNA methylation-mediating effects were mostly studied with respect to the occurrence and development of cardiovascular 29,30 and other diseases. 15,31 The conclusions were similar to the present 32 The increase of S-adenosine homocysteinemia is related to DNA hypomethylation, 33 and Hcy is a byproduct of the methyltransferase reaction.…”

Identification of NLRP3 Inflammation-Related Gene Promoter Hypomethylation in Diabetic Retinopathy

“…It has been reported that a lower level of total methy-lation in NLRP3 promoter was associated with a 17.78-fold increase in risk for micro-and macrovascular complications in T2D. 30 As discussed earlier, the CpG sites in the gene promoter region were usually adjacent to transcription factor binding sites. As such, hypomethylation in the promoter may cause increased gene expression.…”

Size and Shape of Associations of OGTT as Well as Mediating Effects on Adverse Pregnancy Outcomes Among Women With Gestational Diabetes Mellitus: Population-Based Study From Southern Han Chinese

“…Additional path model analysis of mediating effects was used to evaluate associations among age, OGTT and adverse outcomes in GDM patients. We used to employ this method in our previous studies to identify mediating effect among age, gene promoter methylation level and type 2 diabetes mellitus (T2DM) vascular complications (22). Because adverse outcome was binary variable, we used Bayesian analysis method to get the standardized regression coefficients a, b, c ′ and c which identify relationships between variables (23) (in the model the variables are a, direct association between independent and mediator variable; b, direct association between mediator and dependent variable; c ′ , direct association between independent and dependent variable; c, total association between independent and dependent variables; ab, indirect effect; c ′ , direct effect; c, total effect; and (ab/c) * 100%, mediating effect generated by the mediator variable in the dependent variable outcome caused by the independent variable).…”