Update 2013
Neurologist Alastair Compston and his organization, The International Multiple Sclerosis Genetics Consortium, are in the news again, with their newly discovered 48 genetic variants which they proport directly influence the risk of MS. They also say that all of these genes underline the central role of the immune system in MS.
But other researchers are questioning this claim.
Here's a thought-provoking review, published in Elselvier's Multiple Sclerosis and Related Disorders on Science Direct. Written by neuroscientist Christopher Hawkes, it is entitled:
Multiple Sclerosis genetics is dead.
http://www.sciencedirect.com/science/article/pii/S2211034812001551
Hawkes refers to several twin studies of MS in which only one of a pair of identical twins has MS.
I wrote about one such study back in 2011---when Dr. Compston was in the news saying his genetic studies would stop the CCSVI theory, and put the focus back on the immune system, where it belonged. He claimed his genetic discovery would "quell the hysteria" of vascular research, and put an end to it all.
http://www.theglobeandmail.com/life/health-and-fitness/massive-study-disputes-zamboni-theory-of-multiple-sclerosis/article590119/
The discovery strongly suggests MS originates as an inflammatory immune response and casts aside “eccentric and maverick ideas” that it is caused by venous abnormalities, said Alastair Compston, neurology professor at the University of Cambridge and a joint lead author of the study.
“One can say that this provides absolutely no support whatsoever for that [blocked veins] idea,” Prof. Compston said.
But Compston was wrong---it's 2013 and we're still looking at venous hemodynamics, and the genetic connection to the immune system is far from definitive.
Here's what I wrote a couple years ago about genetics and MS.
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Even though Dr. Alastair Compston may continue to assert that his research proves a genetic correlation to the HLA locus and to immune cell activation in MS, there is one thing he cannot explain.
Identical twins.
A recent study of 3 sets of indentical twins, (called "MZ twins" for monozygotic) where one twin had MS, and the sibling did not, brought forward the following information:
There was no discernable genetic difference between the immune system of the twin with MS, and the twin without MS.
Here, we report the genome sequences of one MS-discordant MZ twin pair and messenger RNA (mRNA) transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant, MZ twin pairs. No reproducible differences were detected between co-twins among ~3.6 million single nucleotide polymorphisms (SNPs) or ~0.2 million insertion-deletion polymorphisms (indels). Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and indel genotypes, or expression of ~19,000 genes in CD4+ T cells. Only two to 176 differences in methylation of ~2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to ~800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or normal and cancerous tissues. In the first systematic effort to estimate sequence variation among MZ co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first female, twin and autoimmune disease individual genome sequences reported.
We sought genetic, epigenetic or transcriptomic differences between CD4+ T cells of twin siblings that might explain MS-discordance. While MS is a neurologic disease, T cells are fundamentally involved in its pathophysiology1. However, no reproducible differences in SNPs, indels, CNVs, gene expression levels or sequences aligning to viral genomes were detected between CD4+ T cells of co-twins.
Other epigenetic mechanisms, differences within lymphocyte subsets, mono-allelic differences or other tissues were not examined. These caveats aside, however, MZ twins lacked genetic, epigenetic or transcriptomic differences in T cells to explain MS-discordance.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862593/
Get that? There was absolutely no difference in CD4 and T cells between the twin with MS and the twin without. How can Dr. Compston assert that MS is about the genetics and the immune system, when the healthy twin had the same, exact immune system, and no MS? Truth is, he can't.
Here's what the researcher who conducted this study said--
“We find no smoking gun on the genetic level,” said National Center for Genome Resources geneticist Stephen Kingsmore, co-author of the study published April 28 in Nature.
The research cost $1.5 million, and the scientists took 18 months to sequence 2.8 billion DNA units in each twin, and determine whether they came from the mother or father. Most genomic comparisons look for differences in a just handful of suspect genes, and even whole-genome approaches don’t differentiate between parental contributions.
The researchers also analyzed the twins’ CD4 cells, a type of white blood cell that plays a central role in the development of MS. In these cells, the researchers sequenced epigenomes — chemical instructions that turn genes on and off — and transcriptomes, or a chemical record of genes that are actively coding proteins.
These multiple layers of information represent the cutting edge of genomic analysis, and are expected to reveal what rougher tools cannot. “This was a technical tour de force, and potentially represents a new way of looking at disease states,” said Kingsmore. Nevertheless, they found no differences.
http://www.wired.com/wiredscience/2010/04/multiple-sclerosis-twinmystery/
No genetic difference in the immune system of the twin with MS and the twin without.
Maybe the researchers should look at venous malformations? Or environmental factors which influence the endothelium?
One environmental factor in twins with MS has been studied---vitamin D.
Each of the nine sun exposure–related activities during childhood seemed to convey a strong protection against MS within MZ twin pairs.
http://www.wellnesspasadena.com/Vitamin%20d%20research/Childhood_sun_exposure_influences_risk_of_multiple_sclerosis_in_monozygotic_twins_--_Islam_et_al._69__4___381_--_Neurology_01.pdf
we need more research into environment and epigenetic factors involved in developing MS.
Joan
