Veteran study helps decode GWI phenotypes

To paraphrase Winston Churchill, Gulf War Illness (GWI) is a mystery wrapped in an enigma—a complex interplay of multiple symptoms, caused by a variety of environmental and chemical hazards. To make things more difficult, there are no diagnostic biomarkers or objective laboratory tests with which to confirm a GWI case. Instead, clinicians rely on patients’ reports of symptoms and the absence of other explanations for the symptoms.

Looking to provide more information on the epidemiology and biology of GWI, US Department of Veterans Affairs (VA) researchers analyzed data from the VA Cooperative Studies Program 2006/Million Veteran Program 029 cohort, the largest sample of GW-era veterans available for research to date: 35,902 veterans, of whom 13,107 deployed to a post 9/11 Persian Gulf conflict.

The researchers used the Kansas (KS) and Centers for Disease Control and Prevention (CDC) definitions of GWI, both of which are based on patient self-reports. The KS GWI criteria for phenotype KS Sym+ require ≥ 2 mild symptoms or ≥ 1 moderate or severe symptoms in at least 3 of 6 domains: fatigue/sleep problems, pain, neurologic/cognitive/mood, gastrointestinal, respiratory, and skin. The criteria for phenotype KS Sym+/Dx- also exclude some diagnosed health conditions, such as cancer, diabetes mellitus, and heart disease. The researchers examined both of these phenotypes.

They also used 2 phenotypes of the CDC definition: CDC GWI is met if the veteran reports ≥ 1 symptoms in 2 of 3 domains (fatigue, musculoskeletal, and mood/cognition). The second, CDC GWI severe, is met if the veteran rates ≥ 1 symptoms as severe in ≥ 2 domains.

Of the veterans studied, 67.1% met the KS Sym+ phenotype; 21.5% met the KS Sym+/Dx– definition. A majority (81.1%) met the CDC GWI phenotype; 18.6% met the severe phenotype. The most prevalent KS GWI domains were neurologic/cognitive/mood (81.9%), fatigue/sleep problems (73.9%), and pain (71.5%).

Although their findings mainly laid a foundation for further research, the researchers pointed to some potential new avenues for exploration. For instance, “Importantly,” the researchers say, “we consistently observed that deployed relative to nondeployed veterans had higher odds of meeting each GWI phenotype.” For both deployed and nondeployed veterans, those who served in the Army or Marine Corps had higher odds of meeting the KS Sym+, CDC GWI, and CDC GWI severe phenotypes. Among the deployed, Reservists had higher odds of CDC GWI and CDC GWI severe than did active-duty veterans.

Their findings also revealed that older age was associated with lower odds of meeting the GWI phenotypes. “[S]omewhat surprisingly,” they note, this finding held in both nondeployed and deployed samples, even after adjusting for military rank during the war. The researchers cite other research that has suggested younger service members are at greater risk for GWI (because they’re more likely, for example, to be exposed to deployment-related toxins). Most studies, the researchers note, have shown GWI and related symptoms to be more common among enlisted personnel than officers. Biomarkers of aging, such as epigenetic age acceleration, they suggest, “may be useful in untangling the relationship between age and GWI case status.” 

Because they separately examined the association of demographic characteristics with the GWI phenotypes, the researchers also found that women, regardless of deployment status, had higher odds of meeting the GWI phenotypes compared with men.

Their findings will be used, the researchers say, “to understand how genetic variation is associated with the GWI phenotypes and to identify potential pathophysiologic underpinnings of GWI, pleiotropy with other traits, and gene by environment interactions.” With information from this large dataset of GW-era veterans, they will have a “powerful tool” for in-depth study of exposures and underlying genetic susceptibility to GWI—studies that could not be performed, they say, without the full description of the GWI phenotypes they have documented.

The study had several strengths, the researchers say. For example, unlike previous studies, this one had a sample size large enough to allow more representation of subpopulations, including age, sex, race, ethnicity, education, and military service. The researchers also collected data from surveys, especially data on veterans’ self-reported symptoms and other information “incompletely and infrequently documented in medical records.”

Finally, the data for the study were collected more than 27 years after the GW. It, therefore, gives an “updated, detailed description” of symptoms and conditions affecting GW-era veterans, decades after their return from service.

To paraphrase Winston Churchill, Gulf War Illness (GWI) is a mystery wrapped in an enigma—a complex interplay of multiple symptoms, caused by a variety of environmental and chemical hazards. To make things more difficult, there are no diagnostic biomarkers or objective laboratory tests with which to confirm a GWI case. Instead, clinicians rely on patients’ reports of symptoms and the absence of other explanations for the symptoms.

Looking to provide more information on the epidemiology and biology of GWI, US Department of Veterans Affairs (VA) researchers analyzed data from the VA Cooperative Studies Program 2006/Million Veteran Program 029 cohort, the largest sample of GW-era veterans available for research to date: 35,902 veterans, of whom 13,107 deployed to a post 9/11 Persian Gulf conflict.

The researchers used the Kansas (KS) and Centers for Disease Control and Prevention (CDC) definitions of GWI, both of which are based on patient self-reports. The KS GWI criteria for phenotype KS Sym+ require ≥ 2 mild symptoms or ≥ 1 moderate or severe symptoms in at least 3 of 6 domains: fatigue/sleep problems, pain, neurologic/cognitive/mood, gastrointestinal, respiratory, and skin. The criteria for phenotype KS Sym+/Dx- also exclude some diagnosed health conditions, such as cancer, diabetes mellitus, and heart disease. The researchers examined both of these phenotypes.

They also used 2 phenotypes of the CDC definition: CDC GWI is met if the veteran reports ≥ 1 symptoms in 2 of 3 domains (fatigue, musculoskeletal, and mood/cognition). The second, CDC GWI severe, is met if the veteran rates ≥ 1 symptoms as severe in ≥ 2 domains.

Of the veterans studied, 67.1% met the KS Sym+ phenotype; 21.5% met the KS Sym+/Dx– definition. A majority (81.1%) met the CDC GWI phenotype; 18.6% met the severe phenotype. The most prevalent KS GWI domains were neurologic/cognitive/mood (81.9%), fatigue/sleep problems (73.9%), and pain (71.5%).

Although their findings mainly laid a foundation for further research, the researchers pointed to some potential new avenues for exploration. For instance, “Importantly,” the researchers say, “we consistently observed that deployed relative to nondeployed veterans had higher odds of meeting each GWI phenotype.” For both deployed and nondeployed veterans, those who served in the Army or Marine Corps had higher odds of meeting the KS Sym+, CDC GWI, and CDC GWI severe phenotypes. Among the deployed, Reservists had higher odds of CDC GWI and CDC GWI severe than did active-duty veterans.

Their findings also revealed that older age was associated with lower odds of meeting the GWI phenotypes. “[S]omewhat surprisingly,” they note, this finding held in both nondeployed and deployed samples, even after adjusting for military rank during the war. The researchers cite other research that has suggested younger service members are at greater risk for GWI (because they’re more likely, for example, to be exposed to deployment-related toxins). Most studies, the researchers note, have shown GWI and related symptoms to be more common among enlisted personnel than officers. Biomarkers of aging, such as epigenetic age acceleration, they suggest, “may be useful in untangling the relationship between age and GWI case status.” 

Because they separately examined the association of demographic characteristics with the GWI phenotypes, the researchers also found that women, regardless of deployment status, had higher odds of meeting the GWI phenotypes compared with men.

Their findings will be used, the researchers say, “to understand how genetic variation is associated with the GWI phenotypes and to identify potential pathophysiologic underpinnings of GWI, pleiotropy with other traits, and gene by environment interactions.” With information from this large dataset of GW-era veterans, they will have a “powerful tool” for in-depth study of exposures and underlying genetic susceptibility to GWI—studies that could not be performed, they say, without the full description of the GWI phenotypes they have documented.

The study had several strengths, the researchers say. For example, unlike previous studies, this one had a sample size large enough to allow more representation of subpopulations, including age, sex, race, ethnicity, education, and military service. The researchers also collected data from surveys, especially data on veterans’ self-reported symptoms and other information “incompletely and infrequently documented in medical records.”

Finally, the data for the study were collected more than 27 years after the GW. It, therefore, gives an “updated, detailed description” of symptoms and conditions affecting GW-era veterans, decades after their return from service.

To paraphrase Winston Churchill, Gulf War Illness (GWI) is a mystery wrapped in an enigma—a complex interplay of multiple symptoms, caused by a variety of environmental and chemical hazards. To make things more difficult, there are no diagnostic biomarkers or objective laboratory tests with which to confirm a GWI case. Instead, clinicians rely on patients’ reports of symptoms and the absence of other explanations for the symptoms.

Looking to provide more information on the epidemiology and biology of GWI, US Department of Veterans Affairs (VA) researchers analyzed data from the VA Cooperative Studies Program 2006/Million Veteran Program 029 cohort, the largest sample of GW-era veterans available for research to date: 35,902 veterans, of whom 13,107 deployed to a post 9/11 Persian Gulf conflict.

The researchers used the Kansas (KS) and Centers for Disease Control and Prevention (CDC) definitions of GWI, both of which are based on patient self-reports. The KS GWI criteria for phenotype KS Sym+ require ≥ 2 mild symptoms or ≥ 1 moderate or severe symptoms in at least 3 of 6 domains: fatigue/sleep problems, pain, neurologic/cognitive/mood, gastrointestinal, respiratory, and skin. The criteria for phenotype KS Sym+/Dx- also exclude some diagnosed health conditions, such as cancer, diabetes mellitus, and heart disease. The researchers examined both of these phenotypes.

They also used 2 phenotypes of the CDC definition: CDC GWI is met if the veteran reports ≥ 1 symptoms in 2 of 3 domains (fatigue, musculoskeletal, and mood/cognition). The second, CDC GWI severe, is met if the veteran rates ≥ 1 symptoms as severe in ≥ 2 domains.

Of the veterans studied, 67.1% met the KS Sym+ phenotype; 21.5% met the KS Sym+/Dx– definition. A majority (81.1%) met the CDC GWI phenotype; 18.6% met the severe phenotype. The most prevalent KS GWI domains were neurologic/cognitive/mood (81.9%), fatigue/sleep problems (73.9%), and pain (71.5%).

Although their findings mainly laid a foundation for further research, the researchers pointed to some potential new avenues for exploration. For instance, “Importantly,” the researchers say, “we consistently observed that deployed relative to nondeployed veterans had higher odds of meeting each GWI phenotype.” For both deployed and nondeployed veterans, those who served in the Army or Marine Corps had higher odds of meeting the KS Sym+, CDC GWI, and CDC GWI severe phenotypes. Among the deployed, Reservists had higher odds of CDC GWI and CDC GWI severe than did active-duty veterans.

Their findings also revealed that older age was associated with lower odds of meeting the GWI phenotypes. “[S]omewhat surprisingly,” they note, this finding held in both nondeployed and deployed samples, even after adjusting for military rank during the war. The researchers cite other research that has suggested younger service members are at greater risk for GWI (because they’re more likely, for example, to be exposed to deployment-related toxins). Most studies, the researchers note, have shown GWI and related symptoms to be more common among enlisted personnel than officers. Biomarkers of aging, such as epigenetic age acceleration, they suggest, “may be useful in untangling the relationship between age and GWI case status.” 

Because they separately examined the association of demographic characteristics with the GWI phenotypes, the researchers also found that women, regardless of deployment status, had higher odds of meeting the GWI phenotypes compared with men.

Their findings will be used, the researchers say, “to understand how genetic variation is associated with the GWI phenotypes and to identify potential pathophysiologic underpinnings of GWI, pleiotropy with other traits, and gene by environment interactions.” With information from this large dataset of GW-era veterans, they will have a “powerful tool” for in-depth study of exposures and underlying genetic susceptibility to GWI—studies that could not be performed, they say, without the full description of the GWI phenotypes they have documented.

The study had several strengths, the researchers say. For example, unlike previous studies, this one had a sample size large enough to allow more representation of subpopulations, including age, sex, race, ethnicity, education, and military service. The researchers also collected data from surveys, especially data on veterans’ self-reported symptoms and other information “incompletely and infrequently documented in medical records.”

Finally, the data for the study were collected more than 27 years after the GW. It, therefore, gives an “updated, detailed description” of symptoms and conditions affecting GW-era veterans, decades after their return from service.