Polygenic Risk, Agent Orange Exposure, and Lymphoid Neoplasms in the Veterans Affairs Million Veteran Program.

Importance: Agent Orange (AO), a toxic herbicide mixture contaminated with carcinogenic dioxin, was widely used during the Vietnam War. Although epidemiologic evidence suggests AO exposure is associated with increased lymphoid malignant neoplasm risk, the details of this association and its potential interaction with genetic factors remain unclear. Objective: To evaluate (1) whether AO exposure was associated with increased risk of lymphoid malignant neoplasms, (2) associations of polygenic risk scores (PRSs) in specific lymphoid malignant neoplasms, and (3) whether there was a genetic component × exposure interaction associated with increased risk of developing lymphoid malignant neoplasms. Design, Setting, and Participants: A case-control study of 255 155 US veterans enrolled in the Veterans Affairs Million Veteran Program was conducted with available genotype, AO exposure information, and lymphoid malignant neoplasm diagnosis from January 1, 1965, through June 11, 2024. Exposures: AO exposure status (based on self-reported survey) and PRS derived from genome-wide association studies of lymphoid malignant neoplasms. Main Outcomes and Measures: Risk of developing lymphoid malignant neoplasm subtypes: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and multiple myeloma. Results: A total of 255 155 non-Hispanic White veterans (median [IQR] age, 67 [61-74] years; 235 895 [92.5%] male) with both PRS and AO data were included in this study. AO exposure was associated with an increased risk of chronic lymphocytic leukemia (odds ratio [OR], 1.61; 95% CI, 1.40-1.84), diffuse large B-cell lymphoma (OR, 1.26; 95% CI, 1.03-1.53), follicular lymphoma (OR, 1.71; 95% CI, 1.39-2.11), and multiple myeloma (OR, 1.58; 95% CI, 1.35-1.86). Similarly, PRS was associated with all subtypes: chronic lymphocytic leukemia (OR, 1.81; 95% CI, 1.70-1.93), diffuse large B-cell lymphoma (OR, 1.12; 95% CI, 1.02-1.21), follicular lymphoma (OR, 1.33; 95% CI, 1.21-1.47), marginal zone lymphoma (OR, 1.17; 95% CI, 1.04-1.32), and multiple myeloma (OR, 1.41; 95% CI, 1.31-1.52). No significant PRS × AO interactions were observed. Conclusions and Relevance: To date, this is the largest case-control study of AO exposure and risk of lymphoid malignant neoplasm subtypes and the only study to investigate an AO × gene association with risk. The study found independent associations of both genetic predisposition and AO exposure on several lymphoid malignant neoplasm subtypes.