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

ANZgene

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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.

Original languageEnglish
Article numbere1005853
JournalPLoS Genetics
Volume12
Issue number3
DOIs
Publication statusPublished - 1 Mar 2016

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HLA-DRB1 Chains
sclerosis
Multiple Sclerosis
polymorphism
gene
nervous system
Demyelinating Diseases
disease course
loci
genetic polymorphism
central nervous system diseases
risk reduction
Disease Susceptibility
Receptor Protein-Tyrosine Kinases
Genetic Polymorphisms
Genetic Predisposition to Disease
monocytes
Genes
tyrosine
Monocytes

Cite this

@article{ff777e2e719445d2ba77f081c27cafd0,
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.",
author = "ANZgene and Binder, {Michele D.} and Fox, {Andrew D.} and Daniel Merlo and Johnson, {Laura J.} and Lauren Giuffrida and Calvert, {Sarah E.} and Rainer Akkermann and Ma, {Gerry Z.M.} and Perera, {Ashwyn A.} and Gresle, {Melissa M.} and Louise Laverick and Grace Foo and Fabis-Pedrini, {Marzena J.} and Timothy Spelman and Jordan, {Margaret A.} and Baxter, {Alan G.} and Simon Foote and Helmut Butzkueven and Kilpatrick, {Trevor J.} and Judith Field and Kermode, {Allan G.} and Booth, {David R.} and Booth, {David R.} and Deborah Mason and Stewart, {Graeme J.} and Jac Charlesworth and James Wiley and Jeannette Lechner-Scott and Lotti Tajouri and Lyn Griffiths and Mark Slee and Brown, {Matthew A.} and Pablo Moscato and William MCarroll and Simon Broadley and Steve Vucic and William MCarroll",
year = "2016",
month = "3",
day = "1",
doi = "10.1371/journal.pgen.1005853",
language = "English",
volume = "12",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
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}

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

In: PLoS Genetics, Vol. 12, No. 3, e1005853, 01.03.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

AU - ANZgene

AU - Binder, Michele D.

AU - Fox, Andrew D.

AU - Merlo, Daniel

AU - Johnson, Laura J.

AU - Giuffrida, Lauren

AU - Calvert, Sarah E.

AU - Akkermann, Rainer

AU - Ma, Gerry Z.M.

AU - Perera, Ashwyn A.

AU - Gresle, Melissa M.

AU - Laverick, Louise

AU - Foo, Grace

AU - Fabis-Pedrini, Marzena J.

AU - Spelman, Timothy

AU - Jordan, Margaret A.

AU - Baxter, Alan G.

AU - Foote, Simon

AU - Butzkueven, Helmut

AU - Kilpatrick, Trevor J.

AU - Field, Judith

AU - Kermode, Allan G.

AU - Booth, David R.

AU - Booth, David R.

AU - Mason, Deborah

AU - Stewart, Graeme J.

AU - Charlesworth, Jac

AU - Wiley, James

AU - Lechner-Scott, Jeannette

AU - Tajouri, Lotti

AU - Griffiths, Lyn

AU - Slee, Mark

AU - Brown, Matthew A.

AU - Moscato, Pablo

AU - MCarroll, William

AU - Broadley, Simon

AU - Vucic, Steve

AU - MCarroll, William

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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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DO - 10.1371/journal.pgen.1005853

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