Genetics and MS

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Genetics and MS

Postby OddDuck » Wed Oct 13, 2004 4:16 am

A leading authority of genetics and multiple sclerosis, David A. Hafler, from the Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, recently published an article. I'm pasting an excerpt here. The complete article can be found at: http://www.pubmedcentral.nih.gov/articl ... d=15067307.

Wesley: If you read this, I still think that you might consider contacting Dr. Hafler.

Deb

Copyright © 2004, American Society for Clinical Investigation
J Clin Invest. 2004 March 15; 113 (6): 788–794
DOI: 10.1172/JCI200421357


Multiple sclerosis

David A. Hafler
"....
What remains unknown: the genetic basis of MS

In summary of over a century of research on MS, the scientific community has demonstrated that MS is a complex genetic inflammatory disease of the CNS white matter accompanied by T cell, B cell, and macrophage infiltration; the antigenic target of these immune cells is not certain, but are likely to be common myelin antigens shown to be encephalitogenic in the EAE model. To date, the MHC gene region is the only area of the human genome clearly associated with the disease, though the precise genes in that region responsible for MS are not as yet known. In the same way that Charcot and then others defined the key features of MS by simply examining brain pathology and observing inflammation, it is critical to redefine the molecular pathology of inflammatory human disease in terms of germline DNA sequence based on the haplotype map, transcription products by RNA microarrays (72), and translation products by tandem mass spectrometry. The combination of such approaches will likely generate a new series of hypotheses that can be examined by both animal and in vitro models of human disease. As MS is a complex genetic disease, understanding which combinations of genes provide the multitude of perhaps relatively minor risk factors which in the population as a whole provide protection from microbial disease but together, in unfortunate random combinations, result in human autoimmune disease is a central goal of present research efforts.

New approaches to understanding the genetic basis of MS


Approximately 15–20% of MS patients have a family history of MS, but large extended pedigrees are uncommon, with most MS families having no more than two or three affected individuals. Studies in twins (6–10, 12, 13) and conjugal pairs (73) indicate that much of this familial clustering is the result of shared genetic risk factors, while studies of migrants (74) and apparent epidemics (75) indicate a clear role for environmental factors. Detailed population-based studies of familial recurrence risk (76–78 ) have provided estimates for familial clustering with λs, the ratio of the risk of disease in the siblings of an affected individual compared with the general population equal to approximately 20–40 (79, 80). It has become clear that this represents a complex genetic disease with no clear mode of inheritance.

Genetic diseases may fundamentally be divided into two types. First are the “gene disruptions,” where there is a gene mutation or deletion, which exhibits high penetrance, and where there is the emergence of a clear clinical phenotype. Sickle cell anemia and muscular dystrophy are two such examples with mutations of the hemoglobin and dystrophin genes, respectively. In these diseases, linkage studies, i.e., linking rather large segments of the human genome identified by so-called microsatellite markers among family members with the disease, followed by positional cloning of the disease gene, have been a powerful tool in human genetics. Such studies in families with multiple sib pairs with MS have been less successful. Specifically, to date, the only confirmed genetic feature to emerge from these efforts is the association and linkage of the disease with alleles and haplotypes from the MHC on chromosome 6p21 (81–86). In the mid 1990s, whole genome screens for linkage (87–89) were published. While these investigations have continued to accumulate whole genome linkage data and almost all of these screens have found more regions of potential linkage than would be expected by chance alone, no other clearly statistically significant region has emerged by linkage investigations.

The other types of genetic diseases are more complex; an alternative hypothesis emerging from the linkage studies is that MS, as a common disease, is caused by common allelic variants each with only subtle but important variations in function. Put another way, crude theoretical modeling of human population history suggested that variants which have a high population frequency as a whole, and are likely to be responsible for complex traits (the common disease–common variant hypothesis), will generally be very old and therefore accompanied by rather little linkage disequilibrium (90). Quantitatively, this may translate to dozens of gene regions each with risk factors of less than ×1.1–×1.4 but which in concert lead to major risk for disease development. It may be postulated that as populations emerged out of Africa 30,000 to 50,000 years ago, exposure to new microbes resulted in what are thought to be major population bottlenecks, with survival of individuals with allelic variants allowing for resistance to the novel infectious event. These combinations of different genes providing resistance to the population, when randomly coming together, result in a hyper-responsive immune system, with subsequent autoimmune diseases the price an individual may pay for protection of the general population. Organ specificity may have emerged because each infectious agent evolved with a population bottleneck would select for a single “MHC restricting” element and subsequent antigen specificity.

Identifying the common allelic variants that may underlie such common diseases requires a different approach from linkage studies. One method might be to actually sequence the whole genome among a group of 5,000 patients with MS as compared to an equal number of healthy controls. While this would be the most sensitive approach, as all variants would be identified, at this stage of technology it would be impossible to even consider. It could be argued that as there appear to be only about 10 million variant, single nucleotide polymorphisms (SNPs) in the population, we could just examine those in the patients with disease compared to control subjects. This would also be far beyond present technologies. The possible emerging solution is both elegant and simple, and is based on a recent observation that was in fact suggested by studies of the MHC region over a decade ago. The discovery is that genetic variants tend to occur together in what are called “haplotype blocks.” That is, recent investigations (91) have shown that recombination is not uniformly distributed along chromosomes, as previously assumed, but rather is concentrated in hot spots that are on average some 20 to 40kb apart (haplotype blocks). It has also been shown that in Europeans and Americans of European descent there is very little haplotype diversity within these genomic haplotype blocks (92). Again, this extensive linkage disequilibrium is most probably the consequence of a severe population bottleneck affecting Europeans some 30,000 to 50,000 years ago (93). The European population is thus ideal for screening for association of allelic variants with disease, since very few SNP markers from each of these linkage disequilibrium blocks will be required to screen the entire genome (94). It is expected that there will be approximately 100,000 such haplotype blocks. Assuming that three SNPs are required to interrogate fully the haplotype diversity associated with each block, the whole genome could be screened using approximately 300,000 SNPs (~10% of all SNPs). This approach has been used by Rioux, Daly, Lander, and coworkers to identify the IBD5 locus in a previously identified linkage peak in patients with inflammatory bowel disease (95).

A whole genome association scan, while attractive, is only beginning to be feasible as the cost of genotyping continues to decrease. It is also possible that such an approach may fail because MS may be the result of more than the one genetic syndrome that it is generally believed to be or that hundreds or even thousands of genes, each representing only a fractional risk factor, are associated with the occurrence of MS. Epistatic effects of genes will also complicate the analysis. Nevertheless, large, properly powered experiments will definitively answer the question as to issues of disease heterogeneity and relative risk factors, and will prevent the wasting of resources on underpowered investigations that may provide no definitive answers.

The formation of international consortiums, which allow significant collections of patients, combined with high-throughput genotyping will be critical in performing whole genome scans based on the haplotype map. These collaborative efforts, although using many resources, will be necessary in providing a true road map for rational drug discovery. In this regard, the International MS Genetic Consortium was created two years ago by institutions around the globe including the University of Cambridge, the University of California at San Francisco, Duke University, Vanderbilt University, Harvard Medical School, the Massachusetts Institute of Technology, and the Brigham and Women's Hospital. These new partnerships in medical science requiring collaborations across scientific disciplines and medical institutions will challenge the fabric of funding, authorships, and scientific credit that have traditionally defined academic success. Finally, unlike “gene knockout diseases” which require gene therapy that has been difficult to achieve clinically, elucidation of specific pathways will likely require only minor modification of allelic gene functions. Studies in the EAE model have indicated that modification of only a few gene loci are required to eliminate disease risk. Thus, pharmacologic targeting of relatively few pathways (with proper safeguards for privacy) in populations screened for disease risk may be the ultimate treatment for both the inflammatory and degenerative components of MS. ...."
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Postby art » Fri Oct 15, 2004 5:03 am

If you get in touch with David, I'd love to hear what you find out. I've spoken to him a number of times over the past 3 years (since they announced the haplotype project). I think it is a promising avenue that needs to be explored, but is unlikely to yeild major results in MS due to being underpowered for a highly multi-genic disease (and is probably a number of different diseases on top of that). Almost 3 years ago he confidently asserted to me that they'd be done in 18 months - yet I think they are still raising money and yet to start (I don't know this as fact, but it's what I can deduce from news reports).

I've noticed that his publications on genetics over the past 3 years have amounted to little more than "reviews" of the status quo in genetics with a major slant to supporting the premise of his project. They read more like product literature than science to me.

I bring this up merely to alert people to the fact that there can often be a political flavor to publications that isn't always obvious. I'm not trying to detract from the haplotype effort, which I believe to be one of the better concepts in MS today, but rather to provide a little back-story on something you'll surely be reading more about.

By the way, the whole haplotype concept was developed by a physicist turned geneticist in Eric Lander's lab at the Whitehead named Mark Daly who is a really great guy. I think the approach is going to crack a number of diseases open. Let's hope MS is one of them.
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Postby OddDuck » Fri Oct 15, 2004 8:48 am

Hi, Art! Where you been?? :P

Yes, I noticed what you mentioned. Hafler did mention in a few of his recent publications (just slipped it in there - hard to notice) where funding is a big issue. And I see that the website he refers to in the post I did above leads to nowhere (or at least didn't when I tried it last night). So maybe it didn't get off the ground (yet).

It "appears" (note I say "appears") that the majority of Hafler's funding is coming from the NMSS - I think I saw where it was a little under a mil. And with what he's trying to do, I'd say that isn't much.

Like Wesley said he noticed, things in MS sort of tend to "stall". (Wesley used the term ossified. That's a good description.) I've tried to follow several researchers' work over a certain time-frame chronologically, and I see time and again, where it just plain either flattens out or stalls.

You think it is the political playing field at work? As you know, I don't doubt it, because I work in the doggoned middle of it.

I had just hoped, maybe, that at least in research (call me naive, I guess), that wouldn't happen.....or at least not as much.

And Art!! If you talk to these guys, too, why aren't YOU telling them about us? LOL I do......every time I see one of them, I tell them about the others whom I know AND I tell them about this website. Just like telling Sam Hunter about Wesley! LOL

Maybe I AM just "loud". 8) HAH!

Deb

EDIT: Sorry, Art. That didn't sound good, did it? I didn't mean it like it sounded. You're doing a whole heck of a lot more than I am in MS! I think I'm at a frustration point on what I should do next, is all. I feel like I should be "doing" something more, ya know?
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Postby art » Fri Oct 15, 2004 9:25 am

I've been around - I check in every few days. Tend to post only when I think I know something or my hot buttons get pressed. :-) I *do* mention this site. I haven't spoken to David in a long time - we had a little bit of a row the last time.

As to politics in science - there's more politics than research from what I see. In any human endeavor that has lots of competition for few resources you will generate more politics than work.

As to the haplotype map, Eric Lander told me he figured it would cost around $20M to do (David told me it would cost around $2M and when I told him what Eric said he claimed I needed to give him an order of magnitude lee-way because he's a scientist!) So I think they are still scrambling for funding. But if Eric Lander can't get it, nobody can. He's a pretty impressive guy. (He was the academic leader for the Human Genome Project).
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Postby OddDuck » Fri Oct 15, 2004 9:40 am

Geez, Art, you and David sound like me and Sam! HAH! TOO funny! I wonder if Sam and David are still speaking to each other then!? I've noticed the "hot spots" in medical "relations", too. hehehe.........

Yea, I was afraid of that. I'd guess that Lander is closer to his estimate for funding. I know Sam said "Do you know how many MILLIONS it costs to do research?" Actually, yes I do. I had to keep track of a 100 mil budget just for the "D" side of R&D when I was in corporate.

Yes, I see what you're saying about politics. Man, you'd think with the job I have, I'd be able to make enough noise about all this, wouldn't you? The thing is, the MS cause is a little far removed from the industrial side that I'm in currently.

Well, I'll give it some more thought. Who knows what windows of opportunity may crop up, huh?

Nice to hear from you, Art!!! Don't be such a stranger!! "When you think you know something"..........geez, don't underestimate yourself!! :wink: I know better than that one!

Deb
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