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PLXNA3 Variant rs5945430 is Associated with Severe Clinical Course in Male Multiple Sclerosis Patients

Moaz Qureshi1, Mohamed Hatem1, Raed Alroughani2,3

  • 1Postgraduate Medical Sciences Program, Faculty of Medicine, Kuwait University, Jabriya, Kuwait.

Neuromolecular Medicine
|May 25, 2017
PubMed

Insights

A genetic variant in the PLXNA3 gene is linked to increased multiple sclerosis (MS) severity in males. Lower estradiol levels may contribute to this sex bias in MS progression.

Area of Science:

  • Genetics
  • Neurology
  • Endocrinology

Background:

  • Multiple sclerosis (MS) shows a notable sex bias, with males experiencing a more severe and progressive disease course.
  • Factors contributing to this male-specific MS severity remain largely unknown.
  • Understanding the genetic and hormonal underpinnings of MS sex bias is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify genetic factors associated with male-specific progressive multiple sclerosis.
  • To investigate the role of the PLXNA3 gene and its variants in MS disease severity.
  • To explore the relationship between estradiol levels, PLXNA3 expression, and MS clinical outcomes in both sexes.

Main Methods:

  • Cross-sectional study of 213 Kuwaiti MS patients.
  • Exome sequencing to identify genetic variants.
  • Genotyping of the rs5945430 variant in the PLXNA3 gene using Taqman assay.
  • Enzyme-linked immunosorbent assay (ELISA) to measure serum estradiol levels.

Main Results:

  • A missense variant, rs5945430, in the Plexin A3 (PLXNA3) gene (Xq28) was associated with male-specific MS severity.
  • Genotyping confirmed that the rs5945430G allele significantly increased disease severity (p=0.013) and disability (p=0.024) in male MS patients.
  • Lower estradiol levels were observed in MS males compared to MS females, and these levels were even lower in males with the rs5945430G variant, suggesting a potential protective role for estradiol in females.

Conclusions:

  • The PLXNA3 rs5945430G variant is a significant genetic factor associated with increased disease severity in male multiple sclerosis patients.
  • Estradiol may act as a protective factor by modulating the expression of the PLXNA3 rs5945430G variant in female MS patients.
  • Further research is warranted to elucidate the precise mechanisms underlying this sex-specific genetic influence in MS.
Keywords:
EstradiolExome analysisMultiple sclerosisPlexin A3Sex bias

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