Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
From the Florey Institute of Neuroscience and Mental Health (M.D.B., E.C.N., E.M., C.D., V.L., A.-L.P., T.J.K.); Department of Anatomy and Physiology (M.D.B.), University of Melbourne, Parkville; Crux Biolabs (E.C.N.), Bayswater; Department of Neurology (C.D.), Royal Melbourne Hospital, Parkville; Department of Neurology (A.X., J.L.-S.), John Hunter Hospital, Newcastle; Hunter Medical Research Institute (A.X., J.L.-S.), University of Newcastle, New South Wales Genomics Research Centre (R.A.L.), Centre of Genomics and Personalised Health, Queensland University of Technology; and Menzies Institute for Medical Research (B.V.T.), University of Tasmania, Hobart, Australia.
Published: March 2024
AI Article Synopsis
Article Abstract
Background And Objectives: HLA-DRB1*15:01 (DR15) and are 2 risk genes for multiple sclerosis (MS). The variant rs7422195 is an expression quantitative trait locus for MERTK in CD14 monocytes; cells with phagocytic and immunomodulatory potential. We aimed to understand how drivers of disease risk and pathogenesis vary with HLA and MERTK genotype and disease activity.
Methods: We investigated how proportions of monocytes vary with HLA and genotype and disease activity in MS. CD14 monocytes were isolated from patients with MS at relapse (n = 40) and 3 months later (n = 23). Healthy controls (HCs) underwent 2 blood collections 3 months apart. Immunophenotypic profiling of monocytes was performed by flow cytometry. Methylation of 35 CpG sites within and near the gene was assessed in whole blood samples of individuals experiencing their first episode of clinical CNS demyelination (n = 204) and matched HCs (n = 345) using an Illumina EPIC array.
Results: DR15-positive patients had lower proportions of CD14 MERTK+ monocytes than DR15-negative patients, independent of genotype at the SNP rs7422195. Proportions of CD14 MERTK+ monocytes were further reduced during relapse in DR15-positive but not DR15-negative patients. Patients homozygous for the major G allele at rs7422195 exhibited higher proportions of CD14 MERTK+ monocytes at both relapse and remission compared with controls. We observed that increased methylation of the gene was significantly associated with the presence of DR15.
Discussion: DR15 and MERTK genotype independently influence proportions of CD14 MERTK+ monocytes in MS. We confirmed previous observations that the MERTK risk SNP rs7422195 is associated with altered MERTK expression in monocytes. We identified that expression of MERTK is stratified by disease in people homozygous for the major G allele of rs7422195. The finding that the proportion of CD14 MERTK+ monocytes is reduced in DR15-positive individuals supports prior data identifying genetic links between these 2 loci in influencing MS risk. DR15 genotype-dependent alterations in methylation of the gene provides a molecular link between these loci and identifies a potential mechanism by which MERTK expression is influenced by DR15. This links DR15 haplotype to MS susceptibility beyond direct influence on antigen presentation and suggests the need for HLA-based stratification of approaches to MERTK as a therapeutic target.
