Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
AuthorBinder, MD; Fox, AD; Merlo, D; Johnson, LJ; Giuffrida, L; Calvert, SE; Akkermann, R; Ma, GZM; Perera, AA; Gresle, MM; ...
Source TitlePLOS GENETICS
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sGresle, Melissa; Butzkueven, Helmut; Binder, Michele; Laverick, Louise; Kilpatrick, Trevor; Field, Judith; Spelman, Timothy; PERERA, ASHWYN; Johnson, Laura; MERLO, DANIEL; ...
AffiliationFlorey Department of Neuroscience and Mental Health
Medicine, Dentistry & Health Sciences
Melbourne Medical School
Medicine (RMH Academic Centre)
Clinical School (Royal Melbourne Hospital)
School of Biomedical Sciences
Anatomy and Neuroscience
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsBinder, MD; Fox, AD; Merlo, D; Johnson, LJ; Giuffrida, L; Calvert, SE; Akkermann, R; Ma, GZM; Perera, AA; Gresle, MM; Laverick, L; Foo, G; Fabis-Pedrini, MJ; Spelman, T; Jordan, MA; Baxter, AG; Foote, S; Butzkueven, H; Kilpatrick, TJ; Field, J, Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status, PLOS GENETICS, 2016, 12 (3)
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798184
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.
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- Florey Department of Neuroscience and Mental Health - Research Publications 
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- Medicine (RMH Academic Centre) - Research Publications 
- Clinical School (Royal Melbourne Hospital) - Research Publications 
- Medicine (RMH) - Research Publications 
- School of Biomedical Sciences - Research Publications 
- Anatomy and Neuroscience - Research Publications 
- Pathology - Research Publications 
- Sir Peter MacCallum Department of Oncology - Research Publications