Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

• Differences in Human Leukocyte Antigen distinguished veterans with Gulf War Illness (GWI) from healthy Gulf War era veterans.
• Veterans with GWI show genetic susceptibility which is associated with increased severity of hallmark symptoms of GWI.A large number of Gulf War veterans suffer from diffuse and debilitating symptoms that resemble altered immune functioning. This study evaluated whether the Human Leukocyte Antigen (HLA) gene, which is central to immune functioning, differs between veterans with GWI and unaffected Gulf War veterans. The findings highlight robust differences in HLA composition between the two groups and suggest that veterans with GWI are characterized by genetic susceptibility that confers risk for typical GWI symptoms. These findings provide compelling genetic evidence of immune dysfunction in GWI.

BackgroundGulf War Illness (GWI) is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that Human Leukocyte Antigen (HLA) composition might differ between veterans with and without GWI.MethodsWe identified 144 unique alleles of Class I and II HLA genes in 82 veterans (66 with and 16 without GWI). We tested the hypothesis that a subset of HLA alleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established GWI criteria, and an overall symptom severity was calculated.FindingsWe found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66 GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies.InterpretationThese results indicate a reduced HLA protection (i.e. genetic susceptibility) in veterans with GWI.FundingUniversity of Minnesota and U.S. Department of Veterans Affairs.