Common and low Frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

Binder, Michele D., Fox, Andrew D., Merlo, Daniel, Johnson, Laura J., Giuffrida, Lauren, Calvert, Sarah E., Akkermann, Rainer, Ma, Gerry Z.M., Perera, Ashwyn A., Gresle, Melissa M., Laverick, Louise, Foo, Grace, Fabis-Pedrini, Marzena J., Spelman, Timothy, Jordan, Margaret A., Baxter, Alan G., Foote, Simon, Butzkueven, Helmut, Kilpatrick, Trevor J., and Field, Judith (2016) 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, 12 (3). pp. 1-25.

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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.

Item ID: 43978
Item Type: Article (Refereed Research - C1)
Additional Information:

© 2016 Binder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ISSN: 1553-7390
Funders: National Multiple Sclerosis Society (USA) (NMSS US), Multiple Sclerosis Research Australia (MSRA), National Health and Medical Research Council (NHMRC), Australian Research Council (ARC), Victorian Government
Projects and Grants: NMSS US 6007629, MSRA 13-013, NHMRC APP1032486, ARC LP110100473
Date Deposited: 04 May 2016 07:31
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060410 Neurogenetics @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1109 Neurosciences > 110904 Neurology and Neuromuscular Diseases @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 50%
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