Genome Wide Association Studies Evaluating Response to Interferon Beta in Multiple Sclerosis: A Systematic Review

IntroductionMultiple sclerosis (MS) is an autoimmune demyelinating chronic inflammatory disease of the central nervous system. It affects up to 2.5 million people worldwide , representing a major cause of neurological... [ view full abstract ]

Introduction

Multiple sclerosis (MS) is an autoimmune demyelinating chronic inflammatory disease of the central nervous system. It affects up to 2.5 million people worldwide , representing a major cause of neurological disability in young adults.¹ Interferon beta(IF-B) has been used for decades as the initial therapy for relapsing remitting MS, it’s recommended along fingolimod and glatiramer acetate as first line therapy options.² However, response to IF-B varies among patients with relapse reduction rates ranging from 30-50%. Identification of pharmacogenetic markers controlling response to IF-B may thus pave the way to predict a patient’s response, aiming to achieve earlier control of MS symptoms, progression, and avoiding side effects.  

Methods

A systematic review of GWAS evaluating response to IF-B was conducted according to PRISMA guidelines. A search strategy of PUBMED, GWAS Central, Google Scholar and manual search identified all published English language  genome wide association studies evaluating response to IF-B in MS  from 2000-2018. Selection criteria included:  treatment with interferon beta for a minimum of 2 years and periodical neurological assessment of response using a validated scale (e.g: Expanded Disability Status Scale (EDSS) score).

Results  Seven studies were initially selected for review, one was removed during the review process. The studies differed in their definition of a genome wide significant association(only two studies used the current accepted standard of P < 5 × 10^-8). Several SNPS in  genes  potentially associated with response to interferon-beta (mainly involved in inflammatory pathways active in MS ) were detected, including: GRIA3(significant SNPs in 2 studies), NINJ2, GPC5, HAPLN1, FHIT, GAPVD1, ADAR , IFNAR2 and an SNP within the human leukocyte antigen coding region.Three zinc finger proteins encoding genes were also associated with response (ZFAT, ZHFX4 and ZNF697). An association between a genetic variant in a SLC9A9 gene (influences T cells differentiation) and non response was also detected.  

Conclusion

This review highlights the need for larger genome wide association studies, with  larger sample sizes to validate significant gene associated with response to IF-B  in multiple sclerosis. A meta-analysis of published studies may  provide a mean of detecting genes with larger effects on patients’ response.