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

Autor: Simon J. Foote, Michele D. Binder, Lauren Giuffrida, Alan G. Baxter, Margaret A. Jordan, Trevor J. Kilpatrick, Daniel Merlo, Tim Spelman, Melissa Gresle, Louise Laverick, Andrew Fox, ANZgene, Marzena J. Fabis-Pedrini, Rainer Akkermann, Sarah E. Calvert, Gerry Z. M. Ma, Ashwyn A. Perera, Laura J. Johnson, Helmut Butzkueven, Grace Foo, Judith Field
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Heredity
Molecular biology
Gene Expression
Genome-wide association study
Monocytes
White Blood Cells
Sequencing techniques
Gene Frequency
Animal Cells
Risk Factors
Demyelinating disease
Medicine and Health Sciences
Genetics (clinical)
Genetics
Neurodegenerative Diseases
RNA sequencing
MERTK Gene
Genetic Mapping
Neurology
Cellular Types
Research Article
Multiple Sclerosis
lcsh:QH426-470
Immune Cells
Immunology
Variant Genotypes
Biology
C-Mer Tyrosine Kinase
Polymorphism
Single Nucleotide
Autoimmune Diseases
03 medical and health sciences
Proto-Oncogene Proteins
medicine
Genetic predisposition
Humans
Genetic Predisposition to Disease
Ecology
Evolution
Behavior and Systematics
Alleles
Genetic Association Studies
Evolutionary Biology
Blood Cells
Population Biology
c-Mer Tyrosine Kinase
GAS6
Multiple sclerosis
Biology and Life Sciences
Receptor Protein-Tyrosine Kinases
Cell Biology
MERTK
medicine.disease
Demyelinating Disorders
Research and analysis methods
lcsh:Genetics
030104 developmental biology
Molecular biology techniques
Haplotypes
Gene Expression Regulation
Genetic Loci
Clinical Immunology
Clinical Medicine
Population Genetics
HLA-DRB1 Chains
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 3, p e1005853 (2016)
ISSN: 1553-7404
1553-7390
Popis: 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.
Author Summary Multiple sclerosis (MS) is the most common neurological disease of young Caucasian adults. Oligodendrocytes are the key cell type damaged in MS, a process that is accompanied by loss of the myelin sheath that these cells produce, resulting in demyelination and ultimately in secondary damage to nerve cells. Susceptibility to MS is strongly influenced by genes, and over 100 genes have now been linked with the risk of developing MS. However, surprisingly little is known about the biological mechanism by which any one of these genes increases the probability of developing MS. In this study we have explored in detail the links between one known MS risk gene, MERTK, and MS susceptibility. We found that a number of different alterations in the MERTK gene are independently associated with the risk of developing MS. One these changes was also linked with changes in the level of expression of MERTK in monocytes, an immune cell type known to be involved in the etiology of MS. In an unexpected result, we found this expression-linked alteration in MERTK was either protective or risk-associated, depending on the genotype of the individual at another well known MS risk gene known as HLA-DRB1. In addition, we found that not only were alterations in MERTK associated with MS susceptibility, but potentially with ongoing disease course, indicating that MERTK may be a good target for the development of novel MS therapeutics.
Databáze: OpenAIRE
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