PON1 Status in Relation to Gulf War Illness: Evidence of Gene–Exposure Interactions from a Multisite Case–Control Study of 1990–1991 Gulf War Veterans

Background: Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990–1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1₁₉₂ variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors. Methods: We evaluated PON1₁₉₂ status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1₁₉₂ subgroups. Exact logistic regression explored effects of exposure combinations in PON1₁₉₂ subgroups. Results: Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782). Conclusion: Study results suggest a complex pattern of PON1₁₉₂ exposures and exposure–exposure interactions in the development of GWI.