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Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness..., 2022, Haley et al

Discussion in ''Conditions related to ME/CFS' news and research' started by Trish, May 14, 2022.

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  1. Trish

    Trish Moderator Staff Member

    Messages:
    52,313
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    UK
    Full 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
    https://ehp.niehs.nih.gov/doi/10.1289/EHP9009

    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 interaction=3.41, 95% confidence interval (CI): 1.20, 9.72] and additive (synergy 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 controls=1.18, 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 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
     
    Trish, May 14, 2022
    #1
    shak8, Peter Trewhitt, Mithriel and 2 others like this.
  2. Trish

    Trish Moderator Staff Member

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    Trish, May 14, 2022
    #2
    Hutan, alktipping and Peter Trewhitt like this.
  3. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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    5,255
    Organophosphate-based pesticides have been linked to a ME-like illness. My understanding is that Sarin is chemically similar to these organophosphates pesticides but much stronger. Now Sarin has been linked to a ME-like syndrome.

    Can this tell us something about what might be going on in ME? That there is some damager that is occurring that is similar to that caused by organophosphate pesticides?

    To clarify, ME is not like acute organophosphate poisoning but appears to be similar to the long term sequelae.
     
    Hoopoe, May 14, 2022
    #3
    Hutan, alktipping, Peter Trewhitt and 1 other person like this.
  4. belbyr

    belbyr Established Member (Voting Rights)

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    Merged thread

    https://scitechdaily.com/after-30-y...sarin-nerve-gas-as-cause-of-gulf-war-illness/

    The researchers tested the samples for variants of a gene called PON1. There are two versions of PON1: the Q variant generates a blood enzyme that efficiently breaks down sarin while the R variant helps the body break down other chemicals but is not efficient at destroying sarin. Everyone carries two copies of PON1, giving them either a QQ, RR or QR genotype.

    For Gulf War veterans with the QQ genotype, hearing nerve agent alarms – a proxy for chemical exposure – raised their chance of developing GWI by 3.75 times. For those with the QR genotype, the alarms raised their chance of GWI by 4.43 times. And for those with two copies of the R gene, inefficient at breaking down sarin, the chance of GWI increased by 8.91 times. Those soldiers with both the RR genotype and low-level sarin exposure were over seven times more likely to get GWI due to the interaction per se, over and above the increase in risk from both risk factors acting alone. For genetic epidemiologists, this number leads to a high degree of confidence that sarin is a causative agent of GWI.

    “Your risk is going up step by step depending on your genotype, because those genes are mediating how well your body inactivates sarin,” said Dr. Haley. “It doesn’t mean you can’t get Gulf War illness if you have the QQ genotype, because even the highest-level genetic protection can be overwhelmed by higher intensity exposure.”
     
    Last edited by a moderator: Dec 30, 2022
    belbyr, Dec 30, 2022
    #4
    shak8, SNT Gatchaman and Hutan like this.
  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SNT Gatchaman, Apr 16, 2023
    #5

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