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Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with

Michele D Binder1,2, Andrew D Fox1,3, Daniel Merlo2

  • 1Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

Plos Genetics
|March 19, 2016
PubMed

Insights

Genetic variants in the MERTK gene influence Multiple Sclerosis (MS) risk and disease course. Specific MERTK polymorphisms affect gene expression, impacting MS susceptibility and progression, particularly in relation to HLA-DRB1*15:01 status.

Area of Science:

  • Neuroimmunology
  • Genetics of Central Nervous System Disorders
  • Molecular Biology of Receptor Tyrosine Kinases

Background:

  • Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with strong genetic components.
  • Over 100 genetic loci are associated with MS susceptibility, but the specific causal variants and mechanisms remain largely undefined.
  • Identifying these variants is critical for understanding MS pathogenesis and developing targeted therapeutics.

Purpose of the Study:

  • To investigate the role of the MERTK gene, a known MS susceptibility factor, in the genetic risk and disease course of Multiple Sclerosis.
  • To identify specific MERTK genetic variants associated with MS susceptibility and their functional consequences.
  • To explore the relationship between MERTK variants, MERTK expression, and MS disease progression, considering interactions with other genetic factors like HLA-DRB1*15:01.

Main Methods:

  • Refined genetic association analysis of MERTK with MS risk, identifying independent common and low-frequency variants.
  • Investigated the association of identified variants with MERTK gene expression in monocytes.
  • Examined the impact of MERTK variants and expression levels on MS susceptibility and disease course, including interactions with HLA-DRB1*15:01.

Main Results:

  • Distinct common and low-frequency MERTK variants are independently associated with Multiple Sclerosis susceptibility.
  • One associated MERTK variant correlates with increased MERTK expression in monocytes.
  • Higher MERTK expression shows a complex association with MS risk and disease course, modulated by HLA-DRB1*15:01 status.

Conclusions:

  • Specific MERTK polymorphisms contribute to MS susceptibility through distinct genetic signals.
  • MERTK transcription levels, influenced by genetic variants, play a role in both MS susceptibility and disease course.
  • The interplay between MERTK variants, MERTK expression, and HLA-DRB1*15:01 status highlights a nuanced genetic architecture influencing MS.

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