Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.

Rab17 mediates differential antigen sorting following efferocytosis and phagocytosis

“…62 Unsurprisingly, defects in efferocytic receptors and signaling molecules are associated with the onset of autoimmune disorders including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, 11, 63, 64 and with chronic inflammatory conditions such as atherosclerosis. 13, 15, 65 However, this regulation must be more nuanced than simply sorting all degraded apoptotic cells away from the MHC class II loading compartment, as apoptotic cells can harbor pathogens and act as vehicles for pathogen dissemination.…”

The Gas6/TAM System and Multiple Sclerosis

“…Recently, the same group reported that one specific variant of MerTK gene, so called rs7422195, has discordant association to MS according to HLA (human leukocyte antigen)-DRB1*15:01 status, being protective in DR15 homozygosity and favouring the disease in the absence of DR15. The minor allele of rs7422195 is also associated to an increased gene and protein expression of MerTK in monocytes and CD4 + cells [105]. Whether this subset of cells was formed by T cells or contaminated by monocytes expressing CD4 is not yet known.…”

Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells

“…GWAS has identified several SNPs in the MERTK gene as independently associated with the risk of developing MS (12, 25). Fine-mapping of the MERTK locus identifies a risk variant that operates in trans with the HLA-DRB1 locus and is associated with higher expression of MerTK in MS patient monocytes (13). This particular SNP (rs7422195) displays discordant association depending on the individual’s HLA-DRB1*15:01 status, conferring increased risk, but converting to a protective effect on an HLA-DRB1*15:01 homozygous background.…”

“…Genome-wide association studies (GWAS) have explained much of MS heritability. Single nucleotide polymorphisms (SNPs) in CYP24A1 and CYP27B1 , which tightly regulate the intracellular levels of calcitriol have been associated with an increased risk of MS (11) (12, 13).…”