Genetic studies in CFS/ME to investigate the potential involvement of the immune system and reveal biomarkers

International molecular and cellular studies have suggested an autoimmune component in CFS/ME. This project addresses whether the immune system plays a role in CFS/ME using a genetic approach. We build on our extensive research experience on the genetics of autoimmune diseases such as arthritis, type 1 diabetes and multiple sclerosis, to answer the question: Is CFS/ME an autoimmune disease? Autoimmune diseases occur because the immune system mistakenly attacks the body's own cells, and the diseases arise due to both hereditary and environmental vulnerability factors. A characteristic common feature is a disease risk associated with certain immune genes. We have established a cohort of hundreds of Norwegian CFS/ME patients and healthy controls to investigate the risks associated with various immune variants. This represents by far the largest cohort to be used for genetic studies in CFS/ME Internationally. We have so far found and published that certain HLA alleles are associated with increased risk of CFS/ME, which supports the notion of an immune involvement. We have also analyzed data from thousands of other gene variants previously found to be involved in autoimmune diseases, and our analyses show that several genome regions are associated with risk of CFS/ME (article 1). We did not find the same potential risk variants associated in a Danish CFS/ME cohort, but found some signs of overlap in the self-reported CFS UK biobank cohort. Article 1 shows that there are potential risk gene-variants in CFS/ME, but that these needs to be investigated further in even larger cohorts of well-defined patients. Furthermore, we have performed a comprehensive screen of the HLA region in order to localize the causal variants (article 2), and the results point in the direction of both HLA and non-HLA genes. Finally, we have studied the T cell receptor alpha gene region that hasve previously been reported to be associated with CFS/ME. T cell receptors interact with the HLA molecules, and are thus of great interest to study in diseases like CFS/ME (article 3). We did not replicate the previous reported findings in the Norwegian CFS/ME patients, which underlines the importance of statistical power as our cohort was ten times larger than the initial publication (article 3). All three articles will be included in the PhD thesis, and are currently published (article 2) or submitted for publishing (article 1. which is in revision, and 3).

Prosjektet har bidratt til økt samarbeid mellom norske ME/CFS-forskere slik at vi har utføre den største genetiske studien på ME/CFS per i dag Internasjonalt. Våre studier har kartlagt at genetikken bak CFS/ME er kompleks og at mange genetiske risikofaktorer spiller inn. Vi har funnet implikasjoner på at immungener kan være involvert. Studiene våre danner et viktig grunnlag for fremtidige genetiske studier. Det store DecodeME prosjektet i England bygger videre på våre funn. De har fulgt nøye med vår forskning og vært motivert av våre resultater. PI Benedicte A Lie er medlem av DecodeME sitt scientific advisory board og bidrar aktivt med innspill til den engelske studien. Dette vil muliggjøre en fremtidig entydig utpeking av involverte gener. Vi har i prosjektet også fått mange tilbakemeldinger på at pasientgruppen er meget takknemlige for at det utføres norsk ME/CFS-forskning og uttrykker at forskningen vår på sykdommen gir håp for forståelse av bakenforliggende faktorer.

In this study, we want to study the etiology of CFS/ME by building on our expertise in immunogenetics of autoimmune diseases, as well as our ongoing studies of classical HLA genes regarding the predisposition to CFS/ME. We have a large and clinically well-characterized patient population (almost 500 cases) where our preliminary results show a significant HLA association. A HLA association is one of the characteristic features of autoimmune diseases, which motivates further immunogenetic studies on CFS/ME. Initially, we will dissect the primary genetic determinants across the human major histocompatibility complex, which harbors hundreds of immunologically important genes. Furthermore, we will test for association of all known autoimmune risk genes to address their involvement in CFS/ME pathogenesis, as well as pointing out the immunological and biological pathways implicated, and examine the overlap with the risk profile between CFS/ME and well-established autoimmune diseases. Finally, we will genetically examine the receptor for HLA on T cells, namely the TRA gene and the role in the predisposition to CFS/ME, both individually and in interaction with their HLA ligands. All genetic findings will be linked to clinical information to see if the genetic risk variants are involved in a specific subgroup of patients. The research will take place in a genetic research team that has decades of experience in similar studies in a variety of autoimmune diseases. We have previously systematically mapped the responsible genes in the HLA complex and elsewhere in the genome to diseases such as type 1 diabetes, multiple sclerosis and primary sclerosing cholangitis. The results of these genetic studies will gain insight into biological pathway, pathologic cell types and clinical subphenotypes of CFS/ME, and potentially identify useful biomarkers.