Abstract
Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.
Highlights
Multiple Sclerosis (MS) is the most common inflammatory disease of central nervous system (CNS) which affects young adults [1]
Dapple analysis of significant SNPs Our first aim was to assess the extent of protein-protein interaction (PPI) interactions among genes located within genomic regions with definite association with MS susceptibility
We showed that genetic products coded in loci strongly associated with MS risk substantially interact with each other
Summary
Multiple Sclerosis (MS) is the most common inflammatory disease of central nervous system (CNS) which affects young adults [1]. It is widely acknowledged that genetic factors play an important role in determining the risk of MS [2]. Several epidemiological studies demonstrated an increased frequency of MS among biological relatives of affected individuals [3,4]. Based and association studies have shown that the strongest genetic association in MS is located within the major histocompatibility complex (MHC) class II region [5]. During the last few years Genome Wide Association Studies (GWAS) have identified many other MS associated loci of modest effect located outside the MHC ( more than 50) [7,8,9,10,11]
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