Objective: There has been contradictory evidence about the relationship between Agent Orange (AO) exposure and type 2 diabetes. By combining DNA methylation and DNA genotyping analysis, we intended to determine if AO exposure is related with the development of type 2 diabetes and to confirm the causal association between AO exposure and type 2 diabetes.

Research Designs and Methods: An epigenome-wide association analysis and DNA genotyping analyses were done on the blood of AO-exposed and AO-unexposed type 2 diabetes patients and healthy controls. To assess the causal influence of AO-exposure-identified CpGs on type 2 diabetes, methylation quantitative trait locus (meQTL) and Mendelian randomization (MR) studies were used. The risk of type 2 diabetes was compared between subgroups using polygenic risk score (PRS).

Results: Hypermethylated CpG sites (cg20075319, cg21757266, cg05203217, cg20102280, cg26081717, and cg21878650) and one hypomethylated CpG site (cg07553761) were linked to type 2 diabetes in AO-exposed individuals. Methylation levels at some CpG sites (cg20075319, cg20102280, and cg2608171) were considerably different, according to meQTL analyses. CpG sites discovered in AO-exposed patients were causally linked to type 2 diabetes, according to MR analysis; The impact of the reverse causality was insignificant. A PRS analysis revealed no discernible difference in the risk of type 2 diabetes between AO-exposed and AO-unexposed groups.

Conclusions: We validated a causal relationship between AO exposure and type 2 diabetes by identifying distinct epigenetic markers between AO-exposed and AO-unexposed patients with type 2 diabetes. These results highlight the need for more epigenetic research on the link between type 2 diabetes and AO exposure.


J.Seo: None. Y.Kim: None.


National Research Foundation of Korea (2022R1C1C1002929); Veterans Health Service Medical Center (VHSMC19033); National Institutes of Health; Centers for Disease Control and Prevention (2019-NG-053-02, 2022-NI-067-00)

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