Teng Xueyi, Wan Jia Y, Gupta Pankaj, Li Wei, Cozen Wendy, Ma Helen
Department of Biological Chemistry, School of Medicine, University of California, Irvine.
Department of Epidemiology and Biostatistics, Joe C. Wen School of Population & Public Health, University of California, Irvine.
JAMA Netw Open. 2025 Aug 1;8(8):e2526787. doi: 10.1001/jamanetworkopen.2025.26787.
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.
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.
AO exposure status (based on self-reported survey) and PRS derived from genome-wide association studies of lymphoid malignant neoplasms.
Risk of developing lymphoid malignant neoplasm subtypes: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and multiple myeloma.
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.
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.
橙剂（AO）是一种被致癌二恶英污染的有毒除草剂混合物，在越南战争期间被广泛使用。尽管流行病学证据表明接触橙剂与淋巴恶性肿瘤风险增加有关，但这种关联的细节及其与遗传因素的潜在相互作用仍不清楚。
评估（1）接触橙剂是否与淋巴恶性肿瘤风险增加有关；（2）特定淋巴恶性肿瘤中多基因风险评分（PRS）的关联；（3）是否存在与淋巴恶性肿瘤发生风险增加相关的遗传因素×接触相互作用。
设计、设置和参与者：对参加退伍军人事务部百万退伍军人计划的255155名美国退伍军人进行了一项病例对照研究，研究时间为1965年1月1日至2024年6月11日，具备可用的基因型、橙剂接触信息和淋巴恶性肿瘤诊断结果。
橙剂接触状态（基于自我报告调查）和从淋巴恶性肿瘤全基因组关联研究中得出的PRS。
发生淋巴恶性肿瘤亚型的风险：慢性淋巴细胞白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、边缘区淋巴瘤和多发性骨髓瘤。
本研究纳入了255155名非西班牙裔白人退伍军人（年龄中位数[四分位间距]为67[61 - 74]岁；235895名[92.5%]为男性），他们同时具备PRS和橙剂数据。接触橙剂与慢性淋巴细胞白血病风险增加相关（比值比[OR]，1.61；95%置信区间[CI]，1.40 - 1.84）、弥漫性大B细胞淋巴瘤（OR，1.26；95% CI，1.03 - 1.53）、滤泡性淋巴瘤（OR，1.71；95% CI，1.39 - 2.11）和多发性骨髓瘤（OR，1.58；95% CI，1.35 - 1.86）。同样，PRS与所有亚型相关：慢性淋巴细胞白血病（OR，1.81；95% CI，1.70 - 1.93）、弥漫性大B细胞淋巴瘤（OR，1.12；95% CI，1.02 - 1.21）、滤泡性淋巴瘤（OR，1.33；95% CI，1.21 - 1.47）、边缘区淋巴瘤（OR, 1.17；95% CI，1.04 - 1.32）和多发性骨髓瘤（OR，1.41；95% CI，1.31 - 1.52）。未观察到显著的PRS×橙剂相互作用。
迄今为止，这是关于接触橙剂与淋巴恶性肿瘤亚型风险的最大规模病例对照研究，也是唯一一项调查橙剂×基因与风险关联的研究。该研究发现遗传易感性和接触橙剂在几种淋巴恶性肿瘤亚型上均存在独立关联。
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