Systematic review of genome-wide expression studies in multiple sclerosis

Abstract

Background

Although recent genome-wide association studies have identified several genetic variants contributing to the complex aetiology of multiple sclerosis (MS), expression and functional studies are required to further understand its molecular basis.

Objectives

To identify genes and pathways with differential expression in MS.

Design

The authors conducted a systematic review of seven microarray studies, in which expression in immune cells was compared between MS patients and controls. These studies include a previously unpublished study, which is described here in detail.

Results and conclusion

Although in general the overlap between studies was poor, 229 genes were found to be differentially expressed in MS in at least two studies, of which 11 were in three studies and HSPA1A in four studies. After excluding the authors' unpublished experiment which may have been affected by certain confounding factors and inclusion of treated subjects, 135 genes were identified in at least two studies. The differentially expressed genes were significantly associated with several immunological pathways, including interleukin (IL)-4, IL-6, IL-17 and glucocorticoid receptor signalling pathways. 15 of the 229 loci have shown some association with MS in published genome-wide association studies (p<0.0001), including three loci with confirmed MS risk variants.

Article summary

Article focus

• To identify genes showing differential expression in multiple sclerosis through genome-wide expression profiling in peripheral blood mononuclear cells.

• To conduct a systematic review of genome-wide expression studies in multiple sclerosis in order to identify the most frequently reported genes.

• To identify pathways associated with genes most frequently reported as differentially expressed in multiple sclerosis.

Key messages

• The vast majority of all genes reported as differentially expressed were only identified in a single study.

• However, 229 genes were reported as differentially expressed in MS to the same direction in at least two of the seven studies reviewed, 12 genes of which were in at least three studies.

• After excluding our unpublished experiment. which may have been affected by confounding factors and inclusion of treated subjects, 135 genes were identified in at least two studies.

• The differentially expressed genes were significantly associated with several immunological pathways, including the IL-4, IL-6, IL-17 and glucocorticoid receptor signalling pathways.

Strengths and limitations of this study

• This is the first systematic review of genome-wide expression studies conducted in peripheral immune cells in multiple sclerosis.

• Strict criteria were applied for inclusion of studies, and clearly underpowered studies with fewer than 10 cases or controls were excluded.

• Many of the genes we found to be reported by at least two studies have interesting immunological functions and can be considered promising candidates for further studies.

• However, the studies included should not be considered directly comparable owing to differences in samples, platforms and analyses methods used. In addition, the majority of these studies are small and should be viewed with some caution.

• All studies were conducted in relatively heterogeneous cell populations, and some of the findings could therefore be explained by differences in numbers of different cell populations rather than differential transcriptional activity in MS.

• Finally, our previously unpublished microarray study may have been affected by differences between the labs where the patient and controls samples were prepared for arrays, as well as by the higher mean age of controls. Our study also included four patients who had received immunomodulatory treatment at the time of sample collection.