Variants in Pathways of Genes contribute to Risk of MS

Damotte V, Guillot-Noel L, Patsopoulos NA, Madireddy L, El Behi M; International Multiple Sclerosis Genetics Consortium,A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosissusceptibility. Genes Immun. 2014 Jan. doi: 10.1038/gene.2013.70. [Epub ahead of print]

Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL (LFA-1 CD11a), ICAM1 (CD52) and ICAM3 (CD50)genes, could be of interest to develop novel therapeutic targets.

Genetic studies have identified about 150 genetic variants that can increase your risk of getting MS. However there may be more than this. Some many have too small an effect to jump out at the people doing the studies. However single proteins do not make a cell process and many gene products work together in networks to do this. So genetic variants in a pathway may impact the cell function but do not need to be the same gene to influence the same pathway. So this study looked at molecules they think are involved in cell migration and they came out with the LFA-1-ICAM-1 axis. There is biology to support this as an important pathways not only in cell migration at the blood brain barrier but these are molecules that can be involved in white blood cell activation. Problem is this pathway has been looked at in MS trials and maybe have been chucked away by failure. Were those trials doomed before they started due to the trial design?  Is this the information that people will re-investigate this?

However this makes a lot of sense that variations within pathways of cell function can influence susceptibility and there could be lots of pathways to uncover.

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