Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis.
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SUBMITTER: Taylor K
PROVIDER: S-EPMC10621206 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis.
Taylor Krystyna K Pearson Matthew M Das Sayoni S Sardell Jason J Chocian Karolina K Gardner Steve S
Journal of translational medicine 20231101 1
<h4>Background</h4>Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms.<h4> ...[more]
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Project description:BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients.MethodsWe applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case-control design with 1000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and compared results for overlap and reproducibility.ResultsCombinatorial analysis revealed 199 SNPs mapping to 14 genes that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3 and 5 SNPs. p-values for these communities range from 2.3 × 10-10 to 1.6 × 10-72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS.ConclusionsThis study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients.
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Project description:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of ∼0.2-0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases. Here we critically review existing evidence that genetic factors alter ME/CFS risk before concluding that most ME/CFS candidate gene associations are not replicated by the larger CFS cohort within the UK Biobank. Multiple genome-wide association studies of this cohort also have not yielded consistently significant associations. Ahead of upcoming larger genome-wide association studies, we discuss how these could generate new lines of enquiry into the DNA variants, genes and cell types that are causally involved in ME/CFS disease.
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Project description:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals. To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory immunoglobulin (Ig) A and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG, we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome. We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.
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Project description:Paediatric Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a disabling condition. Schools play a key role in adolescents' experiences with managing ME/CFS. However, little is known about the experiences of adolescents with ME/CFS (and their families) in schools. This paper is an incidental qualitative study, which combines data from two independent ME/CFS studies: study 1 researched ethnic minority adolescents with ME/CFS; study 2 explored Acceptance and Commitment Therapy for adolescents with ME/CFS who had not recovered after one year. Participants included: adolescents with ME/CFS; their families; and medical professionals (ME/CFS specialists and non-specialists). Adolescents, their families, and ME/CFS medical professionals were recruited from a UK specialist paediatric ME/CFS service. Non-ME/CFS medical professionals were recruited from the same region. Semi-structured qualitative interviews and focus groups were undertaken. Participants' views on schools from each study were combined and thematic analysis was used to identify themes. Fifteen adolescents with ME/CFS (11-17 years old), sixteen family members, and ten medical professionals (GPs, school nurses and ME/CFS specialists) were interviewed. Four key themes were found: (1) adolescents identified school was important for aiding ME/CFS recovery, especially educationally and socially; (2) families described varying levels of support from schools and local authorities with help managing ME/CFS - some described significant practical and emotional difficulties to accessing education, whereas others recounted examples of positive supportive strategies, particularly when teachers had previous experience or knowledge of ME/CFS; (3) parents thought three-way communication between schools, healthcare and families could improve support; (4) participants felt schools were an appropriate place for knowledge building and raising awareness of ME/CFS amongst teachers and pupils, to aid improved supportive measures. In conclusion, this paper provides rich data that highlights the importance of education and the realistic fears and hurdles for adolescents with ME/CFS remaining engaged in education and the impact on their future. Some families described positive strategies in school, which were viewed as helpful to manage ME/CFS in the classroom. These strategies could be implemented alongside knowledge building initiatives and improved communication between healthcare and education. There is a need to further investigate useful strategies and determine how teachers can be best supported in implementing them.
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Project description:Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare disorder characterized by uveitis, retinal neovascularization, and retinal degeneration. We sought to describe the course of treated and untreated ADNIV and to identify risk factors for severe vision loss.DesignObservational case series.MethodsClinical data from ADNIV patients from 4 families seen from 1967 through 2019 at a single academic, tertiary referral center were reviewed. The main outcome measures were visual acuity at baseline and follow-up, as well as risk factors for vision loss.ResultsA total of 130 eyes from 65 ADNIV patients (45 female, 20 male; mean age 40.8 years, range 6-77 years) were included. Mean best corrected visual acuity (BCVA) at presentation was LogMAR 0.59 (about Snellen 20/80). Longitudinal analysis included 84 eyes from 42 patients (31 female, 11 male), with mean follow-up of 17.3 years (range 2-43.6 years). Mean BCVA at last follow-up was LogMAR 1.48 (about Snellen 20/600). The disease accelerated in the fifth decade of life, during which the majority of eyes went from normal vision or mild vision loss to at least moderate vision loss (20/70 Snellen equivalent); 25 eyes from 16 patients (29.8%;) showed a steep trajectory of vision loss to no light perception. Tractional retinal detachment was the greatest risk factor for severe vision loss (BCVA <20/200) on multivariable analysis (P < .05).ConclusionsPatients with ADNIV have a high lifetime risk of severe vision loss. Tractional retinal detachment is an important risk factor for poor vision.
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