Abstract
The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.
Highlights
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by medically unexplained fatigue, post-exertional malaise and a variety of additional symptoms, such as chronic pain, sleep disturbances and cognitive difficulties
We performed high resolution human leukocyte antigen (HLA) genotyping by generation sequencing (NGS) in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria[2]
We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 and HLA-DQB1*03:03
Summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by medically unexplained fatigue, post-exertional malaise and a variety of additional symptoms, such as chronic pain, sleep disturbances and cognitive difficulties. ME/CFS has been reported to be partly heritable[12,13], consistent with a multifactorial etiology dependent on both genetic and environmental factors This is the prevailing model for a vast number of diseases, including established autoimmune diseases (AID). Several publications report immunological alterations among ME/CFS patients, e.g. changes in natural killer (NK) cell function[14,15], cytokine levels[16,17], and DNA methylation patterns consistent with immune dysregulation[18] Some of these findings have failed to reproduce in other studies, which could be due to differences in methodology, the complexity and heterogeneity of ME/CFS, and lack of power due to small sample sizes[19]. In this study we aimed to conduct a comprehensive investigation of HLA associations in a large ME/CFS cohort, applying modern, high resolution HLA typing
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