Dysregulation of MS risk genes and pathways at distinct stages of disease

Abstract

Objective: To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.

Methods: We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.

Results: Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage-specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.

Conclusions: Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

Figure 1. Flow chart of the study

CIS = clinically isolated syndrome; DEG = differentially expressed gene; FDR = false discovery rate; GWAS = genome-wide association studies; HC = healthy control; MS = multiple sclerosis; PP-MS = primary progressive MS; RR-MS = relapsing-remitting MS; RT-PCR = real-time PCR; SP-MS = secondary progressive MS.

Figure 2. Dysregulated MS risk genes and pathways at distinct stages of disease

(A) MS susceptibility genes dysregulated at distinct MS stages compared with as measured by Illumina microarrays. (B) Dysregulated MS susceptibility genes validated in 2 distinct array platforms. For A and B, fold-change heatmaps represent upregulated (red), downregulated (green), and unchanged (gray) expressions in the disease group compared with the healthy population. (C) Real-time PCR validation of CD86 transcript in peripheral blood mononuclear cells of a third case-control cohort. Refer also to figure e-2 for data elaboration after removal of a few outliers (samples with expression levels above 500). *p < 0.05, ***p < 0.005. (D) Venn diagram representing number of common and unique enriched pathways for each disease stage. CIS = clinically isolated syndrome; HC = healthy control; MS = multiple sclerosis; PP-MS = primary progressive MS; RR-MS = relapsing-remitting MS; SP-MS = secondary progressive MS.