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.
Highlights
The International Diabetes Federation (IDF) reported that 1 in 11 adults had diabetes (415 million) in 2015, which is predicted to rise to 1 in 10 adults (642 million) by 2040 globally
type 2 diabetes mellitus (T2DM) with macrovascular complications, microvascular complications, and micro-macrovascular complications were more prevalent in the older patients (T2DM alone: 53.43 ± 10.39; T2DM with micro: 60.47 ± 10.78, P = 0.046; T2DM with macro: 63.60 ± 10.29, P = 0.003; T2DM with micro-macro: 64.32 ± 11.98, P = 0.001)
We found that the total methylation in associated specklike protein (ASC), NLRP3 CpG2, NLRP3 CpG3 and three ASC CpGs methylations in T2DM patients without any complication were higher than in T2DM patients with macrovascular complications (P < 0.05)
Summary
The International Diabetes Federation (IDF) reported that 1 in 11 adults had diabetes (415 million) in 2015, which is predicted to rise to 1 in 10 adults (642 million) by 2040 globally. The number of Chinese diabetes patients is the highest in the world (109.6 million in 2015), resulting in a heavy economic burden [2]. T2DM is characterized by damage to insulin secretion and sensitivity, resulting in hyperglycemia, which promotes T2DM micro-macrovascular complications, such as cerebral infarction (DCI) and diabetic retinopathy (DR) [3]. Various host-derived danger signals such as indicators of cell damage (“danger-associated molecular patterns” or DAMPs) and environmental irritants can activate the NLRP3 inflammasome, resulting in IL-1β and IL-18 production [7, 8]. IL-1β and IL-18 maturation and secretion can promote inflammatory immune cell infiltration, contribute to islet β cell death and dysfunction and result in T2DM [5]
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