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The thirtieth anniversary of the 1991 Gulf War has just passed, and much knowledge has been gained about the etiology and pathobiology of GulfWar Illness (GWI) over this time. However, questions still remain about the exact causality of this chronic multisymptom disorder that affects an estimated 250,000 veterans. GulfWar veterans had a unique constellation of exposures to nerve gas agents, pesticides, and other toxicants during the war that have been associated with the disorder. Despite all the work that has been done, questioning of the evidence for a causal role of environmental exposures in GWI persists, driven in large part by the difficulties with conducting epidemiology studies of the role of environmental exposures during the Gulf War. Furthermore, it has remained less clear why some veterans developed the disorder, whereas others with similar exposures did not. The analysis of gene by environment interactions with Gulf War exposures, as the study in the current issue of Environmental Health Perspectives by Haley et al. has done,9 may help address these issues.

Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors. We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism. In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12. An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: -0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes. Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.