HLA-DRB1*15:01 and the MERTK Gene Interact to Selectively Influence the Profile of MERTK-Expressing Monocytes in Both
Michele D Binder1, Eze C Nwoke1, Ellen Morwitch1
1From 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.
Background And Objectives:
HLA-DRB1*15:01 (DR15) and MERTK 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 MERTK 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 MERTK 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 MERTK 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 MERTK 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 MERTK 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.
Insights
Multiple sclerosis risk genes HLA-DRB1*15:01 (DR15) and MERTK influence monocyte proportions. DR15 and MERTK genotype impact CD14+ MERTK+ monocyte levels, with methylation linking DR15 to MERTK expression.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Molecular Genetics
Background:
- Multiple sclerosis (MS) is influenced by genetic risk factors, including HLA-DRB1*15:01 (DR15) and MERTK.
- The MERTK gene variant rs7422195 acts as an expression quantitative trait locus in CD14+ monocytes, which are key immune cells.
- Understanding the interplay between HLA and MERTK genotypes and disease activity is crucial for elucidating MS pathogenesis.
Purpose of the Study:
- To investigate how monocyte proportions vary based on HLA and MERTK genotype in patients with multiple sclerosis.
- To explore the relationship between disease activity (relapse and remission) and monocyte subset distribution.
- To determine the molecular mechanisms linking DR15 and MERTK in MS susceptibility.
Main Methods:
- Flow cytometry was used to analyze immunophenotypic profiles of CD14+ monocytes from MS patients during relapse and remission, and from healthy controls.
- Methylation patterns of the MERTK gene were assessed using an Illumina EPIC array in individuals with first clinical CNS demyelination and matched healthy controls.
- Analysis correlated monocyte proportions and MERTK methylation with HLA-DRB1*15:01 status and MERTK rs7422195 genotype.
Main Results:
- DR15-positive individuals exhibited lower proportions of CD14+ MERTK+ monocytes compared to DR15-negative individuals, irrespective of MERTK rs7422195 genotype.
- Monocyte proportions were further reduced during relapse in DR15-positive MS patients.
- Increased MERTK gene methylation was significantly associated with the presence of DR15, suggesting a molecular link.
Conclusions:
- HLA-DRB1*15:01 and MERTK genotype independently modulate CD14+ MERTK+ monocyte proportions in multiple sclerosis.
- The MERTK risk SNP rs7422195 is confirmed to be associated with altered MERTK expression in monocytes.
- DR15 genotype-associated alterations in MERTK methylation provide a molecular mechanism linking these loci to MS susceptibility beyond antigen presentation.
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