Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms.

Nina L Fransen,Matthew R J Mason,Jörg Hamann,Mark R Mizee,Ester B M Remmerswaal,Inge Huitinga,Joost Smolders,Sabina Luchetti,Jakob B A Crusius,Corbert G Van Eden

doi:10.1111/bpa.12760

Nina L Fransen, Matthew R J Mason + Show 8 more

Open Access

https://doi.org/10.1111/bpa.12760

Copy DOI

Abstract

Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease‐relevant mechanisms. Building on our recent work showing the association of clinical disease course with post‐mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology‐associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T‐allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.

Highlights

Multiple sclerosis (MS) is a heterogeneous disease with large inter-individual differences in disease course and response to immunomodulatory therapies [40, 41]
This analysis shows that six genetic variants show an effect on post-mortem multiple sclerosis (MS) lesion characteristics. rs2234978/FAS, rs11957313/KCNIP1 and rs3130253/MOG genotypes affected the proportion of active lesions, while rs8056098/CLEC16A genotype had an effect on the proportion of mixed active/inactive lesions. rs1064395/NCAN genotype was associated with the incidence of cortical gray matter lesions and rs5742909/ CTLA4 genotype was associated with the proportion of remyelinated lesions
single nucleotide polymorphisms (SNPs) function assessment showed that rs2234978/FAS T allele carriers, which had a higher proportion of active lesions, showed increased FAS gene expression levels in MS autopsy tissue

Summary

Introduction

Multiple sclerosis (MS) is a heterogeneous disease with large inter-individual differences in disease course and response to immunomodulatory therapies [40, 41]. Over the past decades several common genetic variants have been associated with clinical outcome of MS in candidate gene and genome-wide association studies (GWAS) [4, 6, 7, 58]. On their own the identified common genetic variants show a minor effect on the clinical outcome and they have no clinical predictive utility, but they possess an important translational potential [3, 26, 27, 32]. The genes and biological pathways associated with the identified variants remain largely unknown because of the inability to translate genotype into disease-relevant mechanisms [3, 26, 28].

Objectives

Methods

Results

Conclusion