Table_1_Epigenetic link between Agent Orange exposure and type 2 diabetes in Korean veterans.docx

Conflicting findings have been reported regarding the association between Agent Orange (AO) exposure and type 2 diabetes. This study aimed to examine whether AO exposure is associated with the development of type 2 diabetes and to verify the causal relationship between AO exposure and type 2 diabetes by combining DNA methylation with DNA genotype analyses. An epigenome-wide association study and DNA genotype analyses of the blood of AO-exposed and AO-unexposed individuals with type 2 diabetes and that of healthy controls were performed. Methylation quantitative trait locus and Mendelian randomisation analyses were performed to evaluate the causal effect of AO-exposure-identified CpGs on type 2 diabetes. AO-exposed individuals with type 2 diabetes were associated with six hypermethylated CpG sites (cg20075319, cg21757266, cg05203217, cg20102280, cg26081717, and cg21878650) and one hypo-methylated CpG site (cg07553761). Methylation quantitative trait locus analysis showed the methylation levels of some CpG sites (cg20075319, cg20102280, and cg26081717) to be significantly different. Mendelian randomisation analysis showed that CpG sites that were differentially methylated in AO-exposed individuals were causally associated with type 2 diabetes; the reverse causal effect was not significant. These findings reflect the need for further epigenetic studies on the causal relationship between AO exposure and type 2 diabetes.

橙剂（Agent Orange，AO）暴露与2型糖尿病之间的关联，目前已有相互矛盾的研究结论被报道。本研究旨在探讨橙剂暴露与2型糖尿病发病之间的关联，并通过整合DNA甲基化与DNA基因型分析，验证橙剂暴露与2型糖尿病之间的因果关系。本研究对暴露于橙剂与未暴露于橙剂的2型糖尿病患者及健康对照者的血液样本开展了表观全基因组关联研究与DNA基因型分析。随后开展甲基化数量性状位点（methylation quantitative trait locus）分析与孟德尔随机化（Mendelian randomisation）分析，以评估经橙剂暴露筛选出的CpG位点对2型糖尿病的因果效应。合并2型糖尿病的橙剂暴露个体，存在6个高甲基化CpG位点（cg20075319、cg21757266、cg05203217、cg20102280、cg26081717及cg21878650）与1个低甲基化CpG位点（cg07553761）。甲基化数量性状位点分析显示，部分CpG位点（cg20075319、cg20102280及cg26081717）的甲基化水平存在显著差异。孟德尔随机化分析结果表明，橙剂暴露个体中存在甲基化差异的CpG位点与2型糖尿病存在因果关联；反之，2型糖尿病对该类CpG位点的因果效应并不显著。本研究结果提示，仍需开展更多表观遗传学研究，以明确橙剂暴露与2型糖尿病之间的因果关系。