Abstract

Background:

Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias.

Objectives:

We investigated a prestated hypothesis of the association of GWI with a gene–environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure.

Methods:

A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment.

Results:

The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the $\text{interaction}=3.41$; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy $\text{index}=4.71$; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the $\text{controls}=1.18$; 95% CI: 0.81, 1.73; $p=0.35$), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine.

Discussion:

Given gene–environment independence and monotonicity, the unconfounded $\text{aRERI}>0$ supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009

中文翻译：

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评估 PON1 和低水平神经毒剂暴露与海湾战争疾病的基因-环境相互作用：来自美国军事健康调查的全国人口样本的患病率病例对照研究

摘要

背景：

1991 年海湾战争疾病 (GWI) 的病因学共识受到缺乏客观的个人层面环境暴露信息和假设回忆偏差的限制。

目标：

我们研究了 GWI 与对氧磷酶-1 ( PON1 ) Q192R 多态性和低水平神经毒剂暴露的基因-环境 (GxE) 相互作用相关的预设假设。

方法：

从美国军事健康调查的 8,020 名参与者中抽取了 508 个 GWI 病例和 508 个非配对对照的患病率样本，该调查是对海湾战争期间服役的退伍军人的代表性抽样调查。通过实时聚合酶链反应（RT-PCR）测量PON1 Q192R基因型，并用PON1特异性底物测量血清Q和R同工酶活性水平。通过在部署期间听到神经毒剂警报的调查问题来估计低水平的神经毒剂暴露。

结果：

Q192R 基因型和听力警报的 GxE 相互作用与 GWI 的乘法 [患病优势比 (POR)$\text{相互作用}=3.41$; 95% 置信区间 (CI)：1.20, 9.72] 和相加（协同$\text{指数}=4.71$; 95% CI: 1.82, 12.19) 量表，针对测量的混杂因素进行了调整。Q192R 基因型和警报变量是独立的（在$\text{控制}=1.18$; 95% CI：0.81、1.73；$p=0.35$)，GWI 与 R 等位基因数和 Q 同工酶四分位数的相关性是单调的。因交互作用而调整的相对超额风险 (aRERI) 为 7.69 (95% CI: 2.71, 19.13)。在分析中用 Q 同工酶活性代替基因型证实了这一发现。敏感性分析表明，回忆偏差迫使 GxE 交互作用的估计趋于零，并且未测量的混杂不太可能解释这些发现。我们发现 GxE 相互作用涉及 Q 相关的 PON1 重氮磷酶活性和可能的​​弱 GxE 涉及 Khamisiyah 羽流模型，但没有涉及 PON1 R 同工酶活性、芳基酯酶活性、对氧磷酶活性、丁酰胆碱酯酶基因型或酶活性或吡啶斯的明。

讨论：

鉴于基因 - 环境的独立性和单调性，没有混淆的$\text{阿雷里}>0$支持机械交互。连同暴露于化学武器储存设施轰炸产生的沉降物的直接证据以及 Q 同工酶对有机磷酸盐的生化保护的广泛毒理学证据，这些发现为低水平神经毒剂在 GWI 中的病因学作用提供了强有力的证据。https://doi.org/10.1289/EHP9009