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

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Abstract

Multiple sclerosis (MS) exhibits sex bias in disease clinical course as male MS patients develop severe, progressive clinical course with accumulating disability. So far, no factors have been found associating with this sex bias in MS severity. We set out to determine the genetic factor contributing to MS male-specific progressive disease. This is an MS cross-sectional study involving 213 Kuwaiti MS patients recruited at Dasman Diabetes Institute. Exome sequencing was performed on 18 females and 8 male MS patients’ genomic DNA. rs5945430 genotyping was performed using Taqman genotyping assay. Estradiol levels were determined by enzyme-linked immunosorbent assay. Exome analysis revealed a missense variant (rs5945430) in Plexin A3 (PLXNA3) gene (Xq28) associated with male-specific MS severity. Genotyping of 187 MS patients for rs5945430 confirmed the association of rs5945430G with increased disease severity in MS males (p = 0.013; OR 3.8; 95% CI 1.24–11.7) and disability (p = 0.024). Estradiol levels shown to effect PLXNA3 expression were lower in MS males compared to MS females, and they were lower than control rs5945430G males (p = 0.057), whereas MS females had similar estradiol levels to healthy females reducing the level of expressed PLXNA3 GG in MS females. PLXNA3 rs5945430G is associated with increased disease severity in MS male patients. Estradiol is a possible protective factor against the expression of rs5945430G in MS females.

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Acknowledgements

This research was funded by Kuwait Foundation for the Advancement of Science (KFAS) Grant Number 2012-1302-02.

Author’s Contributions

MQ and MH performed DNA extraction and genotyping experiments. SPJ performed the ELISA experiment. RA facilitated patient sample collection and provided clinical data of MS patients. RAA conceived the project’s design, implementation, exome sequencing, data analysis and wrote the manuscript. All authors have reviewed and approved the final manuscript.

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Authors and Affiliations

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

    Moaz Qureshi & Mohamed Hatem

  2. Division of Neurology, Department of Medicine, Amiri Hopsital, Sharq, Kuwait

    Raed Alroughani

  3. Neurology Clinic, Department of Medicine, Dasman Diabetes Institute, Dasman, Kuwait

    Raed Alroughani

  4. Molecular Pathology Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Jabriya, Kuwait

    Sindhu P. Jacob

  5. Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Jabriya, Kuwait

    Rabeah Abbas Al-Temaimi

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  1. Moaz Qureshi
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  3. Raed Alroughani
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Correspondence to Rabeah Abbas Al-Temaimi.

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Qureshi, M., Hatem, M., Alroughani, R. et al. PLXNA3 Variant rs5945430 is Associated with Severe Clinical Course in Male Multiple Sclerosis Patients. Neuromol Med 19, 286–292 (2017). https://doi.org/10.1007/s12017-017-8443-0

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