This Is MS Multiple Sclerosis Knowledge & Support Community

cheerleader wrote:

scorpion wrote:

cheerleader wrote:This thread is suggested reading for those who are referencing Compston's study. Many of the "immunologic" genes associated with MS from the HLA locus have crossover into the vascular realm.

I would suggest asking a genetic specialist about these so called connections instead of relying on anyone on a support forum, including me, to make any kind of scientific connections.

Dr. Ferlini is a genetic specialist, and I have linked her paper, in toto, and her charts above. She spoke about the high level of cross over and "robust correlation" of vascular and immunilogical genes in CCSVI/MS. I merely transcribe and post.

Here is her paper, once again-
http://www.fondazionehilarescere.org/pd ... -final.pdf
thank you,
cheer

Of course you did because she made the connections you want to see. I don't see a bunch of scientists refuting the genetic study we are referring to but of course if you look hard enough you will find what you are looking for. Besides this paper was released in 2010 so I am not sure how it can address the study released last week?

scorpion,
I am not saying Dr. Ferlini refutes the connection of immunological genes of the HLA locus. I am saying that her team expanded on the understanding of these genes, by showing their connection to the venous malformations found in CCSVI. This is how her work expands Dr. Compston's study, since his "new genes" remain on the HLA locus. Unless you have research to prove that she is incorrect, but no one has challenged her findings, and she is still studying this connection in families. Her research shows that these genes go "both ways." Affecting venous malformations and the immune system. Read her paper, check out the charts.

Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs (venous malformations) identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

and I wasn't looking for this research to disprove Compston. I heard Dr. Ferlini speak in Bologna in 2009, and her presentation stayed with me. I thought it was important to repost.
cheer

Genetic connections of stroke, diabetes and heart disease on the HLA locus associated with autoimmune diease--an over-reaction of the immune system, which may have been adventagious when people lived shorter lifespans.

Genetics play a role in susceptibility to infections. Host defenses are modified by genetics, with certain human leukocyte antigen (HLA) classes being more associated with autoimmune responses. A ubiquitous infectious agent thus may cause an inflammatory response in some individuals but not in others. This could explain some of the discrepancies in the literature on the association of infectious agents with atherosclerosis. Polymorphisms of the mannose-binding lectin (MBL) gene, which codes for a protein designed to help facilitate phagocytosis, have been shown to increase the risk of infection in humans. These polymorphisms were also found to correlate with the presence and size of carotid atherosclerotic plaques.[97] Similarly, mutations in the IL-1ra gene modify the risk of coronary artery disease associated with C pneumoniae infection.[98]

Similarly, the toll-like receptor-4 (TLR4) is expressed on macrophages, endothelial cells, and vascular smooth cells. It binds to bacterial lipopolysaccharide and plays an important role in the innate immune response, and it also binds to other ligands, including modified LDL, fibrinogen, and NF-κB. Ligand binding to this receptor initiates an inflammatory cascade, including the release of cytokines, chemokines, and adhesion molecules. The TLR4 polymorphism Asp299Gly is associated with a reduction in inflammatory mediators, atherosclerosis assessed by noninvasive studies, and the risk of clinical events.[5, 99, 100, 101] Defective TLR variations have been observed with an increased incidence of myocardial infarctions.

An innate susceptibility for an inflammatory response is demonstrated through an MHC class II receptor polymorphism. T cells expressing defective binding sites can be activated in a receptor-independent manner. This mechanism can be triggered by multiple infectious agents, including even Staph and Strep antigens.[102]

Taken together, these findings provide evidence that inflammation-related genes play an important role in atherosclerosis. Further work is needed to confirm many of these findings in other populations. The proinflammatory genotype, resulting in a high cytokine response, may have been an evolutionary advantage. In the past, it likely promoted wound healing and eradication of infections during times of nutritional deficiency. In today's society, with longer life spans, these previously advantageous traits may contribute to atherosclerosis and insulin resistance. In the future, therapies directed at down-regulating or inhibiting inflammation may reduce atherosclerosis and its complications, including stroke.

http://emedicine.medscape.com/article/1 ... erview#a30


cheer

Genetics does mean you are doomed from the start. I could have bad genes, bad hygiene, or bad posture (I was thinking about bad blue-jeans, but never mind . Some things can add up to no straightforward answer because of accumulation of secondary damage. Age can worsen all these problems. A saving grace is, invasive therapies can take you some of the way, as a last resort, if they don't kill you. There are several possibly-dangerous technological approaches involving chemotherapy and cell biology. For those who need them, they are good weapons to have available. The sooner problems are addressed, the less chance for damage that can't be fixed.

I am a geneticist who has MS and have also had the CCSVI procedure. Happy to answer ??s.

A geneticist is just what we need...! Welcome. I am surprised.

Do you have any thoughts on Dr. Compston's work or Dr. Ferlini's? Is Cheer right about the shared genes or overlap between the vascular and the immune system?

I am unclear on genetic mechanisms. I thought you were born with a genetic sqquence and it stays the same for your lifetime. Clearly I am wrong and you do things that effect you genetically every day?

Billmeik wrote:I am unclear on genetic mechanisms. I thought you were born with a genetic sqquence and it stays the same for your lifetime. Clearly I am wrong and you do things that effect you genetically every day?

Hi Bill--
hopefully our genetics expert will come back and answer some questions. Until then, read up on epigenetics. This is the environmental factors that switch our genes on and off, and is why identical twins can be different, and one can have MS, the other not. My Dad had an identical twin...Dad had Parkinson's, his brother didn't. Something in my Dad's environment changed his genes....here's how--
http://learn.genetics.utah.edu/content/epigenetics/
cheer

I do not understand the logic of the conclusions of this paper. Could Scorpion please explain why they are logical please.

My understanding is that genes predespose pwMS to MS but some people (identical twins) with the same genes do not get MS. This mplies other factors impact the etiology of MS. This means MS is a multifactorial disease. The Nature reviewereditors appear to have forgotten this basic fact.

MarkW

Hi Mark-
this thread is actually on the genetic crossover paper that Dr. Ferlini presented in Bologna...she found that CCSVI and MS share many copy number variations in the HLA locus associated with MS. She states there is a robust genetic correlation between the two.

I presented this research in contrast to Dr. Compston's paper. Many genes in the HLA locus affect the vasculature and the endothelial lining of blood vessels. And yes, epigenetics and environment are important, as you mention.

Read the thread from the beginning, There is much to learn.
cheer

Hi - I am a university biology student, with only 4 classes left until I graduate. School starts again for me Sept. 1st! I am taking Neuroanatomy and the second semester of Organic Chemistry. Wish me luck...

I just wanted to clarify that we all indeed are born with one genome and that it is the same genome that we have today and will have when we die. It is the complex system of gene expression that allows for so much flexibility, as in identical twins. Gene expression is affected by chemicals that switch genes off at on in different circumstances. Stress, pollution, diet, you name it, can affect how the genes are expressed. Some people have certain beneficial genes, such as HIV resistance, and others are missing beneficial ones, such as the ability for the blood to clot. I should say that rather than "missing," they are actually mutated with protein structures that are better or worse at doing something that they were intended to do. My genetic profile has been decoded, and I have a protein at MS determined loci that is typical of those having MS. The protein is better able to switch on when affected by environmental factors. It is not a guarantee that I would have MS. Epigenetics is an interesting phenomenon that deals with gene memory. Certain genes passed down from our parents may have "memory" of how it had been expressed in our parents. It is thought that this is what we see in obesity and how it runs in families. Behavior seems to be shaped by epigenetics. How our ancestors dealt with their environments gets passed down through gene exression memory. This might include temperament, reactions to stress, the ability to be calm under pressure, nurturing behavior, etc. Sure, we learn these things by watching our parents, but it is thought that they may be the very same behavioral responses that their parents, parents, parents had. This is just my simplistic contribution to the discussion and to those who were wondering if our genomes change or not. Like I said, guanine, adenine, tyrosine and u______ (can't think of the name at the moment, MS brain), are the choices of proteins that we get at each of the locations, and it stays this way. We then either pass the same proteins down to our children, or they get the protein that the other parent passed to them. Getting a certain protein, for example adenine, at a specific location, is either good, bad or indifferent. A protein that I have at a specific location on my genome has been shown to make me more likely to become alcoholic, if I drink, for example. I hope this helps!

Editted to add: One gene can indeed be implicated in more than one problem or occurrance. The genes that have been found to have a similar protein present at a certain loci in many people with MS can also be found to be the gene where a certain protein is present in those with CCSVI. Or Alzheimers, or Lou Gherig's....this would probably indicate that they are related disorders or occurrances. I guess the big question would be when is the switch for gene expression in each of these things triggered to happen? Do they work independently of each other? etc.

Hi Shannon-
thanks for your explanation and for sharing your studies and own MS protein/genetic susceptability connection.
Good luck to you as you finish up your schooling!!
cheer

Thank you Shannon!
I must go to read it again with my MS brain.
Good luck at school
Erika

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 no difference in t cells between the twin with MS and the twin without. How can Dr. Compston assert that MS is about the t cells, when the healthy twin had the same, exact t cells, 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/ ... inmystery/


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?

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 ... ogy_01.pdf
Joan

Billmeik wrote: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 no difference in t cells between the twin with MS and the twin without. How can Dr. Compston assert that MS is about the t cells, when the healthy twin had the same, exact t cells, 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/ ... inmystery/


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?

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 ... ogy_01.pdf
Joan

I wonder what the nine "sun exposure-related activities" in the study were? I mean, I was a sunbather all of my life and my Mom never used sunscreens on me or anything and I still have MS. Research criteria like those used in this study are always questionable to me because it relies on trying to go back throughout someone's life and ask questions like "Did you typically eat cereal for breakfast all of your life, or eggs?"

It's no surprise to me that the identical twins would have the exact same genomes, immune systems, T-cells, etc. They are essentially the exact same people! It is, of course, always a surprise when one twin develops a disease that the other one does not, and definately indicates an environmental reason of some kind for it.

There would also be no epigenetic differences between them, because this process of genetic memory being transferred to progeny is done before the egg splits in two. Therefore, the epigenome (which is still a bit of a controversial concept) would also be exactly the same.

I'm not a genetics expert, only a biology student, but some of the information in this research seems redundant or ambiguous to me.