Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample

@article{Haley2022EvaluationOA,
  title={Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample},
  author={Robert W. Haley and Gerald Kramer and Junhui Xiao and Jill A Dever and John F. Teiber},
  journal={Environmental Health Perspectives},
  year={2022},
  volume={130}
}
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… 
Comment on “Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample”
TLDR
There is an obvious source of bias to account for the association between PON1 genotypes and GWI and the results reported cannot be taken as evidence of a causal effect of lowlevel nerve agent exposure on risk of GWI.
Response to “Comment on ‘Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample’”
TLDR
The important points about the PON1 gene that Curtis raises further demonstrate the great advantages of G×E interaction studies from a causal inference perspective, and although the allele differences by ancestry are a potential source of bias for the main effect of the genotype, the study data actually suggest that they do not bias the G–E interaction.
Response to “Comment on ‘Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey’s National Population Sample’”
TLDR
The sensitivity analysis for unmeasured confounders in the paper demonstrated that the estimated G×E interaction was sufficiently strong that the association between an unme measured confounder and both the environmental exposure and the disease would have to be extremely strong to explain away the finding.
Invited Perspective: Causal Implications of Gene by Environment Studies Applied to Gulf War Illness
The thirtieth anniversary of the 1991 Gulf War has just passed, and much knowledge has been gained about the etiology and pathobiology ofGulfWar Illness (GWI) over this time. However, questions still

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