Agent Orange and Genetic Risk Independently Linked to Lymphoid Malignancies in Veterans

A large-scale case-control study of over 255 000 US veterans has revealed that both exposure to Agent Orange (AO) and a high polygenic risk score are independently associated with increased risk of several mature lymphoid malignancies. The findings, published from the Veterans Affairs Million Veteran Program (MVP), underscore the separate and potentially additive roles of environmental and genetic risk factors in the development of hematologic cancers such as chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM).

Agent Orange, the dioxin-contaminated herbicide used extensively during the Vietnam War, has long been suspected of contributing to cancer risk among veterans. This study offers a detailed and comprehensive evaluation of the association between Agent Orange exposure and lymphoid malignancy, while also factoring in an individual’s inherited genetic susceptibility via polygenic risk scores (PRS).

The analysis leveraged data from the MVP, a biobank initiative representing one of the largest genomic and phenotypic datasets of US veterans. This case-control analysis focused on 255 155 non-Hispanic White participants with complete AO exposure and genotype data, with cancer diagnoses confirmed between 1965 and 2024.

AO exposure was self-reported through VA surveys, and polygenic risk was quantified using genome-wide association study (GWAS)-based scoring for each lymphoma subtype.

Participants had a median age of 67 years old, and over 92% were male, reflecting the demographics of veterans most affected by AO exposure during the Vietnam War.

Analysis showed that AO exposure significantly increased the odds of developing CLL (odds ratio [OR] 1.61), DLBCL (OR 1.26), FL (OR 1.71), and MM (OR 1.58). In parallel, higher PRS also strongly predicted risk: CLL (OR 1.81), DLBCL (OR 1.12), FL (OR 1.33), MM (OR 1.41), and marginal zone lymphoma (MZL) (OR 1.17).

However, despite the clear independent effects, the study found no statistically significant interaction between AO exposure and PRS in any of the cancer subtypes evaluated. In other words, the combination of a high genetic predisposition and AO exposure did not multiply risk beyond the sum of their individual effects.

“These findings suggest that AO exposure and polygenic risk independently contribute to lymphoma malignant neoplasm risk without evidence of interaction, pointing to distinct and potentially additive pathways,” the authors wrote.

For clinicians serving the US veteran population, especially those who served in Vietnam, this study provides valuable clarity on 2 fronts. First, it reinforces AO exposure as a confirmed environmental risk factor across multiple subtypes of lymphoid malignancy. Second, it highlights the relevance of genetic predisposition, even in environmentally influenced cancers, and suggests a role for individualized risk stratification based on both exposure history and inherited risk.

Importantly, while there is no synergistic effect between genetics and exposure, the additive risk could have meaningful implications for screening and early detection efforts.

Reference

Teng X, Wan JY, Gupta P, Li W, Cozen W, Ma H. Polygenic risk, Agent Orange exposure, and lymphoid neoplasms in the Veterans Affairs Million Veteran Program. JAMA Netw Open. 2025;8(8):e2526787. doi:10.1001/jamanetworkopen.2025.26787