A genetic component to the development of CFS has been suggested by various twin studies.14–16
Immune dysfunction studies9,10,22
highlighted cytokine deregulation and immune cell disruption27
as important features in the pathophysiology of the disease. In our current study, we show an increase in the expression of HLA DQA1*01 in patients with CFS. There was also a marginal increase in the expression of HLA-DQB1*06, although the association with CFS disappeared after inclusion of HLA-DQB1*06 as an independent variable in the same logistic regression model as HLA-DQA*01. This suggests that HLA-DQA1*01 may be the primary association with CFS. We also found decreased expression of HLA-DRB1*11 in CFS, although this association was weak and disappeared after correction for all possible comparisons of HLA-DRB1 alleles between patients and controls.
Specific HLA-DQ polymorphisms have been associated with various diseases including diabetes and coeliac disease.28,29
In previous work, Keller et al
found a possible association of HLA-DQ3 with chronic fatigue syndrome,7
but HLA-DQ3 is a broad definition based on serological typing, so any association with disease could not be assigned to specific HLA-DQ alleles. The HLA-DQA1*01 allele has been associated with few disease conditions, although associations have been found with tubulointerstitial nephritis and uveitis syndrome,30
and hyper-response to measles vaccine.31
“Although our results will need independent replication, they do provide possible target HLA alleles to investigate further for association with chronic fatigue syndrome”
Underhill et al
found no association between HLA alleles and CFS.19
However, they did not examine the frequency of the HLA-DQA1 alleles, so it is not possible to make a direct comparison of results. Interestingly, in their study the combined frequency of the HLA-DQB1*0601 and HLA-DQB1*0602 phenotypes was significantly higher in the patients than in the controls (35% v
0.045), if correction for multiple comparisons was omitted. Although not commented upon in the Underhill study, these data are consistent with the marginal increase in HLA-DQB1*06 allele frequency seen in our study, and may be indicative of an increased frequency of HLA-DQA1*01 alleles in linkage disequilibrium. The patients studied by Underhill et al
came from the same clinical service as in our present study, although they were different patients.19
Therefore, any differences between the two studies are unlikely to be explained by selection bias.
HLA-DQB1*06 forms the largest group of HLA-DQB1 molecules,32
and has been associated with several diseases, including narcolepsy33
and multiple sclerosis.34
Interestingly, it has been suggested that narcolepsy, which is strongly associated with HLA-DQB1*0602, may need to be excluded in the differential diagnosis of CFS.35
The marginal increase in HLA-DQB1*06 seen in our study will need to be investigated further. The same is true for the decreased expression of HLA-DRB1*11.
There may be several reasons for the inconsistency seen in studies of HLA molecules and CFS. Early studies used serological typing, which is unable to discriminate between many of the alleles identified by the sequence specific primer/polymerase chain reaction technique used here. Even so, additional subtyping of HLA-DQA1*01 and HLA-DQB1*06 alleles will be necessary to identify which particular subtypes are important. A second major problem is that the few studies that have been carried out have used relatively small numbers of patients with CFS, and may lack sufficient power to show significant differences. Our current study also suffers from this caveat and, although differences between patients and controls were detected, the results need to be treated with caution. In particular, the need for multiple testing at multiallelic loci is a major problem in this type of study, especially when the number of available cases is low. Although our results will need independent replication, they do provide possible target HLA alleles to investigate further for association with CFS.
In conclusion, the current available data on immune cell and cytokine deregulation in CFS are consistent with an immunomodulatory role for the HLA system in this disease. The results of our study provide provisional evidence for an association of CFS with the HLA class II region, and suggest that this may be primarily with the HLA-DQA1*01 allele. However, because of the strong linkage disequilibrium between genes in this region, an association with other genes within the HLA locus cannot be ruled out.
Take home messages
- Our results suggest an association between chronic fatigue syndrome (CFS) and the HLA class II region, primarily the HLA-DQA1*01 allele
- However, because of the strong linkage disequilibrium between genes in this region, an association with other genes within the HLA locus cannot be ruled out
- Further studies are needed to clarify the situation