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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2018.00709

Association analysis on NLRP3 inflammation-related genes promotor methylation as well as mediating effect in T2DM and vascular complications in Southern Han Chinese population

 Zixing Zhou1, Lijun Wang2,  Zihao Wen1, Shaoling Zheng1, Xiaohong Ye1, Dandan Liu1, Jing Wu1, Xiaoqian Zhou1, Yumei Liu1, Yao Wang1, Shirui Dong1, Xiuxia Huang1, Xiuben Du1, Kehui Zhu1, Xiaojing Chen1, Shiqi Huang1, Chengli Zeng1, Yajing Han1,  Baohuan Zhang1, Lihong Nie3*, Guang Yang4, 5* and  CHUNXIA JING1, 5*
  • 1Department of Epidemiology, Jinan University School of Medicine, China
  • 2Department of Nutriology, School of Medicine, Jinan University, China
  • 3Department of Endocrine, The First Affiliated Hospital of Jinan University, China
  • 4Department of Pathophysiology, School of Medicine, Jinan University, China
  • 5Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, China

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.

Keywords: T2DM (Type 2 diabetes mellitus), NLRP3, promoter methylation, Vascular complication, AIM2, ASC

Received: 18 Jul 2018; Accepted: 09 Nov 2018.

Edited by:

Ondřej Šeda, Charles University, Czechia

Reviewed by:

Federico Biscetti, Università Cattolica del Sacro Cuore, Italy
Olivia Belbin, Sant Pau Institute for Biomedical Research, Spain  

Copyright: © 2018 Zhou, Wang, Wen, Zheng, Ye, Liu, Wu, Zhou, Liu, Wang, Dong, Huang, Du, Zhu, Chen, Huang, Zeng, Han, Zhang, Nie, Yang and JING. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Lihong Nie, Department of Endocrine, The First Affiliated Hospital of Jinan University, Guangzhou, China, lihongnie001@outlook.com
Prof. Guang Yang, Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China, guangyangphd@gmail.com
Prof. CHUNXIA JING, Department of Epidemiology, Jinan University School of Medicine, Grang Zhou, China, jcxphd@gmail.com