Low and moderate frequency variants in MERTK are independently associated with Multiple Sclerosis susceptibility with discordant association dependent upon HLA-DRB1*1501 status.
Journal Contribution ResearchOnline@JCUAbstract
Background: Susceptibility to Multiple Sclerosis (MS) is mediated by both genetic and environmental factors. Studies have shown that the family of tyrosine receptor kinases known as the TAMs (Tyro3, Axl, Mertk), play important roles in myelination and immune responses, and genetic variations within MERTK are associated with susceptibility to MS. Objectives: In order to identify functionally relevant variants associated with MS risk, we performed fine mapping of MERTK, as well as expression analyses in immune cell types isolated from people with MS and healthy controls. Methods: We employed a next generation sequencing strategy of individuals selected on the basis of MERTK haplotype to identify potential functional variants, followed by association testing of identified variants, with a particular focus on low frequency and novel variants within MERTK. We performed expression analysis (RNA) and protein analysis (flow cytometry) in immune cell subtypes in conjunction with MERTK genetics to determine the functional consequences of MS risk associated variants. Results: Low and moderate frequency variants within MERTK were independently associated with MS susceptibility. Importantly, our results demonstrated that alternate alleles at the same position within MERTK were associated with MS risk, dependent on HLA-DRB1*1501 haplotype status. Furthermore, MS susceptibility variants in MERTK were associated with altered expression of Mertk in human monocytes. Conclusions: Genetic variants within MERTK are associated with increased risk of MS, and these variants correlate with altered Mertk expression in human monocytes. Altered expression of Mertk, dependent on the allele present and in the context of HLA-DRB1*1501 status, may have consequences for monocyte function and protection against development of MS.
Journal
Multiple Sclerosis Journal
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21
ISBN/ISSN
1477-0970
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Issue
14
Pages Count
1
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Sage Publications
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