Tuesday, 20 January 2015

Is disease progression in your genes?

Why is my MS progressing so fast and Joe Soap seems to be stable? #MSBlog #MSResearch

"The study below makes a bold attempt to look for genetic factors that predict age of onset of MS and severity in PPMSers. The study is underpowered and does not reveal anything significant. Please note that although the p-values in some of the reported analyses look significant  there are so many tests done in a GWAS analysis that the weakly positive associations reported could have occurred by chance."

"When the investigator's lower the hurdle by which they judge significance they make a case for certain biological pathways being involved; these pathways make sense in terms of what we think we know about MS. Interestingly, the so called citrate cycle comes up top, a metabolic pathway that contains fumarate a metabolite that has been shown to have anti-inflammatory effects in relapsing MS and may have neuroprotective effects. Could this pathway be underactive in MS? Another pathway involves B cells; as you are aware B cells are linked to the pathogenesis of MS and may be the key to understanding this disease. There is evidence that the so called ectopic B cell follicles that are typically found in  the meningeal cover of the brain and spinal cord may be involved in driving MS disease progression. I am a B cell fan and I think this cell is what is driving the disease; by chance it is one of the cells that EBV shacks-up in and calls home."

"What do we do with these results? We need to take note and hopefully the International MS genetics consortium will try and reproduce these results; based on statistics a large number of these weak associations will fall away. The bottom line based on this, and other studies, is that the rate of disease progression in MS, does not appear to have a major genetic component, unlike disease susceptibility." 

Epub: Giacalone et al. Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis. Mult Scler. 2015 Jan 12. pii: 1352458514564590. 

BACKGROUND: The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear.

OBJECTIVE: The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS).

METHODS: We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools.

RESULTS: No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: "oxidative phosphorylation" (FDRAAO=9*10-4; FDRMSSS=3.0*10-2), "citrate (TCA) cycle" (FDRAAO=1.6*10-2; FDRMSSS=3.2*10-3), and "B cell receptor signaling" (FDRAAO=3.1*10-2; FDRMSSS=2.2*10-3). In addition, an enrichment of "chemokine signaling pathway" (FDR=9*10-4) for AAO and of "leukocyte transendothelial migration" (FDR=2.4*10-3) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively.

CONCLUSIONS: Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.

1 comment:

  1. "The bottom line based on this, and other studies, is that the rate of disease progression in MS, does not appear to have a major genetic component, unlike disease susceptibility."

    I think there are studies that show if you have infratentorial lesions you are more likely to have a disease that progresses. I don't think lesion location is a random phenomena. Has anyone looked at the geneticsame of lesion location?


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