A recent case–control study found that HLA-DR15 and MERTK genotypes influenced the proportions of MERTK-expressing monocytes in multiple sclerosis.
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. Genetic and environmental factors are implicated in the etiology of MS. HLA-DRB1*15:01 (DR15) and MERTK are two genes associated with the risk for MS. The variant rs7422195 is an expression quantitative trait locus for MERTK expression in CD14+ monocytes.
A study published in Neurology: Neuroimmunology & Neuroinflammation assessed the influence of disease activity and DR15 status on MERTK levels in circulating CD14+ monocytes in MS patients.
Study Population
A total of 34 female and 6 male patients experiencing an MS relapse were recruited, along with 18 healthy controls (HCs). Repeat blood samples were collected from 23 MS patients and 16 HCs after 3 months. The allele frequency at rs7422195 did not deviate significantly from the expected Hardy–Weinberg equilibrium.
MS Patients With GG Genotype at rs7422195 Show Increased CD14+ MERTK+ Monocytes
There was no significant phenotype-dependent difference in the proportion of CD14+ MERTK-positive monocytes at relapse or remission for participants with at least one A-allele at rs7422195. However, among people without the A-allele, there was a two-fold increase in the proportion of CD14+ MERTK+ monocytes in MS patients compared to HCs, irrespective of relapse status. No statistically significant difference was observed in MERTK gene expression between MS patients and HCs, indicating the role of post-transcriptional regulation. There was no upregulation of MERTK expression on CD14+ monocytes of MS patients and HCs in basal RPMI media with or without TGF-β, indicating that TGF-β does not increase MERTK expression on CD14+ monocytes.
DR15 Positivity Reduces CD14+ MERTK+ Monocytes
A significantly lower proportion (0.7-fold) of CD14+ MERTK+ monocytes was observed in HLA-DR15-positive patients versus those who were DR15-negative. This reduction in the proportion of MERTK+ monocytes could not be definitively correlated with genotype at rs7422195, age, or treatment status. The proportions of CD14+ MERTK+ monocytes were compared between DR15-positive and DR15-negative HCs to assess whether the correlation between the DR15 haplotype and MERTK is specific to MS. A trend towards a higher proportion of CD14+ MERTK+ monocytes in DR15-negative HCs was noted.
The DR15 Allele Increases MERTK Methylation in Monocytes
Methylation was then investigated as the potential mechanism underlying the altered expression of MERTK with DR15-positivity. Methylation of 35 CpG sites in and around the MERTK gene was analyzed in the whole blood sample of patients and HCs. No differences in methylation were observed. The data was deconvoluted to analyze methylation within monocytes, which showed significantly altered methylation at nine CpG sites in or around MERTK.
Relapse-Associated CD14+ MERTK+ Monocyte Reduction Depends on DR15 Status
Assessment of the influence of disease activity on the proportion of CD14+ MERTK+ monocytes in MS patients revealed no difference when the cohort was evaluated as a whole or stratified according to MERTK genotype or with DR15-negative status. However, a significant contraction was noted in the proportion of this cellular population at relapse in DR15-positive patients.
Source:
Binder, M. D., Nwoke, E., Morwitch, E., Dwyer, C. L., Li, V., Xavier, A., Lea, R. A., Lechner‐Scott, J., Taylor, B., Ponsonby, A., & Kilpatrick, T. J. (2024). HLA-DRB1*15:01 and the MERTK gene interact to selectively influence the profile of MERTK-Expressing monocytes in both health and MS. Neurology: Neuroimmunology & Neuroinflammation, 11(2). https://doi.org/10.1212/nxi.0000000000200190
