title: 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.
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Binder
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Bioinformatics Core, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Fox
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merlo
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Johnson
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Giuffrida
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvert
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rainer
authors.initials: R
authors.lastname: Akkermann
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gerry Z M
authors.initials: GZ
authors.lastname: Ma
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Ashwyn A
authors.initials: AA
authors.lastname: Perera
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Gresle
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Laverick
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Grace
authors.initials: G
authors.lastname: Foo
authors.affiliation: Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors.forename: Marzena J
authors.initials: MJ
authors.lastname: Fabis-Pedrini
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Spelman
authors.affiliation: Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Jordan
authors.affiliation: Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Baxter
authors.affiliation: John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Foote
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Field
mesh_terms: D005786:Gene Expression Regulation; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors; D000076202:c-Mer Tyrosine Kinase
chemical_list: D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase