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<p>Veterans of the 1990–1991 Gulf War (GW) experienced an elevated burden of chronic health conditions, most notably Gulf War Illness (GWI). While the disease etiology remains unclear, it is hypothesized that both genetic susceptibility and deployment exposures contribute to GWI risk. We investigated 6,882 GW-deployed Veterans, assessing genetic and epigenetic interactions with GW exposures (ground combat, insect baits, oil well smoke exposure, pyridostigmine bromide pills, biological/chemical warfare agents, and pesticides). We observed nominal evidence of a genome-wide gene–environment interaction variance component (0.38 ± 0.22) related to biological/chemical warfare-agent exposure and identified three loci showing genome-wide significant interactions (<i>p</i> &lt; 5 × 10<sup>− 8</sup>; rs78441512, rs145790544, and rs117997207). Also, type-2 diabetes polygenic risk association with GWI is reduced in Veterans exposed to biological/chemical warfare agents, pesticides, and oil well fire smoke during GW deployment. An exploratory computational drug-repurposing analysis highlighted clebopride, rifampicin, and fisetin as compounds potentially targeting GWI-associated molecular pathways. Our GWI epigenome-wide association study identified five sites showing epigenetic interaction with four GW exposures: ground combat, biological/chemical warfare agents, pyridostigmine bromide pill use, and pesticide use. In conclusion, our study demonstrates that both genetic and epigenetic factors interact with GW military exposures to influence GWI vulnerability, highlighting potential druggable pathways to develop novel therapeutic interventions.</p>

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Genomic interplay between deployment exposures and Gulf War illness in Million Veteran Program participants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Dan Qiu,
  • Brenda Cabrera-Mendoza,
  • Jun He,
  • Lea Steele,
  • Rachel Quaden,
  • Kelly M. Harrington,
  • Sarah T. Ahmed,
  • J. Michael Gaziano,
  • Elizabeth J. Gifford,
  • Mihaela Aslan,
  • Drew A. Helmer,
  • Elizabeth R. Hauser,
  • Renato Polimanti,
  • Sumitra Muralidhar,
  • Jennifer Moser,
  • Jennifer E. Deen,
  • Philip S. Tsao,
  • Adriana Hung,
  • Dave Oslin,
  • Deepak Voora,
  • Jessica V. Brewer,
  • Mary T. Brophy,
  • Kelly Cho,
  • Lori Churby,
  • Jacob T. Kean,
  • Saiju Pyarajan,
  • Robert Ringer,
  • Luis E. Selva,
  • Shahpoor Alex Shayan,
  • Brady Stephens,
  • Stacey B. Whitbourne

摘要

Veterans of the 1990–1991 Gulf War (GW) experienced an elevated burden of chronic health conditions, most notably Gulf War Illness (GWI). While the disease etiology remains unclear, it is hypothesized that both genetic susceptibility and deployment exposures contribute to GWI risk. We investigated 6,882 GW-deployed Veterans, assessing genetic and epigenetic interactions with GW exposures (ground combat, insect baits, oil well smoke exposure, pyridostigmine bromide pills, biological/chemical warfare agents, and pesticides). We observed nominal evidence of a genome-wide gene–environment interaction variance component (0.38 ± 0.22) related to biological/chemical warfare-agent exposure and identified three loci showing genome-wide significant interactions (p < 5 × 10− 8; rs78441512, rs145790544, and rs117997207). Also, type-2 diabetes polygenic risk association with GWI is reduced in Veterans exposed to biological/chemical warfare agents, pesticides, and oil well fire smoke during GW deployment. An exploratory computational drug-repurposing analysis highlighted clebopride, rifampicin, and fisetin as compounds potentially targeting GWI-associated molecular pathways. Our GWI epigenome-wide association study identified five sites showing epigenetic interaction with four GW exposures: ground combat, biological/chemical warfare agents, pyridostigmine bromide pill use, and pesticide use. In conclusion, our study demonstrates that both genetic and epigenetic factors interact with GW military exposures to influence GWI vulnerability, highlighting potential druggable pathways to develop novel therapeutic interventions.