A barrier to research is the heterogeneity within cohorts and the inconsistencies in findings between different cohorts making it difficult to compare patients who are thought to share the same illness. One way to overcome this is by subgrouping patients, and a uniform way to do this, at least in part, is through the use of human leukocyte antigen (HLA) typing. HLAs are immune system genes that confer response to environmental exposures (infectious, chemicals, etc.) and risk of disease development, which should make HLAs well-suited for researching cohorts with chronic fatigue syndrome (CFS) and/or multiple chemical sensitivities (MCS). In addition, in other diseases, HLAs have been used successfully to subgroup patients.
1. Because of the differences in definitions and/or exclusionary criteria, findings in CFS often seem contradictory.1 What if the results are not contradictory but instead apply to different subgroups of patients?
Several studies have found a possible association between CFS and/or post-Q fever fatigue syndrome (QFS) and HLA-DR4, HLA-DR5, and/or HLA-DRB1*11 (HLA-DRB1*11 along with HLA-DRB1*12 make up HLA-DR5) vs. others have found a possible association between CFS and HLA-DQB1*06 or HLA-DQA1*01.2-8
Some of these HLAs are not just different but are in some ways mirror opposites in terms of what they confer risk of and protection from, which should aid in their ability to subgroup patients.
While HLA-DR4 has been associated with the risk of some endocrine conditions and dilated cardiomyopathy (DCM), some alleles are less prevalent in and may offer protection from narcolepsy.9-12
While HLA-DQB1*0602 has been associated with narcolepsy and a cohort of patients with CFS or FM and sleep disorders, HLA-DQB1*06, sometimes specifically HLA-DQB1*0602, is less prevalent in and may offer protection from some of the endocrine diseases.6,9,10,12,13
In two CFS cohorts, wherein the frequency of HLA-DQB1*06 was increased, HLA-DR4 and/or HLA-DR11 were decreased, although none of these were at frequencies considered significant.7,8 Nevertheless, this could be consistent with the idea that different definitions and/or criteria may be creating very different subgroups, and HLAs may not only reflect these differences but may be useful, if not necessary, in aiding researchers in extrapolating findings across different cohorts to other patients who fall within a similar subgroup. While the patients in these two cohorts were different, they were from the same clinical services, which could be consistent with the idea that criteria may be creating specific subgroups.7,8
2. Using HLAs to subgroup patients may lessen the need for exclusionary criteria:
When some CFS studies excluded endocrine and/or cardiac diseases as part of their exclusionary criteria, they may have also been inadvertently excluding an important patient group, those with a sudden onset from an infectious trigger.
Viruses are thought to be capable of triggering autoimmune diseases (Hashimoto's thyroiditis and some cases of DCM) in patients with a genetic predisposition.14,15
In the CFS cohort, in which HLA-DR4 and HLA-DR5 were more frequent, all patients also had evidence of viral reactivation.2 In another CFS cohort, in patients with bronchial hyperresponsiveness (BHR), there was a link between recurrent flu-like illness and thyroid inflammation.16 In that cohort, "Patients with BHR presented significantly more often with fatigue that was made worse by physical exercise, recurrent flu-like illness, thyroid inflammation, and painful lymph nodes."16 In a third CFS cohort, there was an association between viruses or incomplete viral replication and abnormal cardiac findings, including sinus tachycardia at rest, oscillating abnormal T-wave flattenings and T-wave inversions, abnormal cardiac-wall motion, and cardiac degenerative findings upon biopsy.17
Conversely, some CFS cohorts are made up primarily of patients with a gradual onset and potentially different symptoms and test results.16-19 Within one CFS cohort, at the start of the study, more patients had a gradual vs. sudden onset (76.9 vs. 20%), unrefreshing sleep vs. unusual fatigue postexertion (95.4 vs. 78.5% ), and been diagnosed or treated for depression vs. CFS (30.8 vs. 13.9%). In addition, only 16.9% had swollen lymph nodes.18 At 3 years' follow-up, 79.2% had unrefreshing sleep and only 33.3% had unusual fatigue postexertion. "At 2 and 3 years follow-up, only 21% of the subjects were classified as having CFS."18
When patients were subgrouped, results were better. In a different study, "Marginal differences were detected in cytokine responses and in cell surface markers in the total CFS population. However, when the patients were subgrouped by type of disease onset (gradual or sudden) or how well they were feeling on the day of testing, more pronounced differences were seen."19 Some of these differences might be due to or associated with differences in HLAs.
3. HLAs have been found to be a link between infectious agents and risk of disease:
"HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in less than 5% of HTLV-1 carriers." "HAM/TSP was significantly associated with HLA-B*07 and HLA-DRB1*01:01," and, "Individuals with these HLA alleles had greater HTLV-1 proviral load than asymptomatic carriers."20
4. HLAs have been found to be a link between other environmental exposures and risk of disease:
In one sarcoidosis study, there was an association between insecticide exposure at work, having HLA-DRB1*1101, and sarcoidosis and possibly between exposure to mold and musty odors, having HLA-DRB1*1101, and sarcoidosis. In addition, there was a possible association between insecticide exposure at work, having HLA-DRB1*1501, and sarcoidosis.21 (In several cohorts, CFS has been associated with HLA-DRB1*11, although the exact alleles and/or whether patients also had comorbid MCS are unknown.4,5)
HLAs have also been associated with beryllium exposure and risk of disease, those who developed chronic beryllium disease (CBD) vs. those who did not.22
5. In other diseases, HLAs have been associated with risk of disease, type of onset, severity of illness, test results, and response to treatment.9,23-26
Researchers have now found differences in HLA amino acid residues between anticitrullinated peptide antibody (ACPA) negative rheumatoid arthritis (RA) vs. ACPA positive RA, " … two amino acid positions, HLA-DRB1 position 11 (in which serine and leucine conferred risk) and HLA-B position 9 (in which aspartate conferred risk) were driving ACPA negative RA. These two positions are already known to drive ACPA positive RA as well, however, the specific amino acid residues conferring risk were completely distinct between the two disease subtypes." They concluded that these results, along with others, suggest, "… ACPA positive and ACPA negative RA are genetically distinct and potentially have separate autoantigens contributing to the pathogenesis."26
In addition, this HLA test method was also able to objectively determine which patients may have actually had other types of arthritis. Of the patients who had been misidentified as ACPA negative RA in these cohorts, an estimated 4% to 11% "most likely had ankylosing spondylitis (AS)."
HLA typing has been used successfully in other conditions and could be used to help subgroup patients with CFS and/or MCS, which may make it easier for researchers to reach findings that are both significant and more able to be extrapolated. Using HLA typing to subgroup patients could be an incredibly important tool in CFS and MCS research.
© 2016 Laurie Dennison Busby, BEd
Laurie Busby received a BEd from the University of Missouri. At age 30, she developed chronic fatigue syndrome and the hypersensitivities that sometimes accompany it. Shortly thereafter, her aunt, a nurse anesthetist, handed her a huge medical dictionary and some studies, insisting that Laurie learn how to read them because she had something with no answers. Since that time, Laurie has asked for several tests that have given her incredible clues about her illness, conducted a family medical health survey among patients, testified before the CFS Advisory Committee to the US Department of Health and Human Services, and started a chronic illness blog, cfsfmmcsandrelatedstudies.tumblr.com, in an attempt to share what she has learned.