Genetic Predisposition

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Genetic Predisposition

Postby Lyon » Sun Sep 16, 2007 4:48 pm

I know I brought this subject up about a year ago but there is no doubt that we have all learned a lot in the time since.

The assumption of genetic predisposition is one of the earliest and longest held assumptions in the history of modern MS research.

The assumption of genetic predisposition was/is based on incidence data showing that MS predominantly, at that time almost exclusively, affected light skinned caucasians, seemingly regardless of location (either side of the equator, in the midst of populations with low MS incidence, etc..)

This led to, what seemed, the logical assumption that darker skinned people had an immunity to MS or that lighter skinned people have a genetic predisposition.

In the years since, the incidence data has changed drastically and a multitude of studies have shown that darker skinned people have no immunity to MS and therefore Caucasians have no genetic predisposition. Despite it seeming otherwise earlier, the situation is as it always was and MS incidence never has been one of genetic predisposition. Human genetics aren't capable of changing that fast.

Because of "familial clustering" I am not so foolish as to think that genetics aren't involved in MS incidence, but it now seems obvious that MS incidence is owed to "environmental predisposition" (as the only alternative to "genetic predisposition") and genetic factors, and possibly other environmental factors are secondary "triggers" (only after environmental predisposition could these triggers enable the MS process to begin).

Considering the situation, I don't see how anyone could make a logical argument for genetic predisposition. If you think you can, I'd love to hear it.

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Postby Jean » Mon Sep 17, 2007 2:02 am

I think MS genetic predisposition is not linked to general genetic pattern anymore. But there's still a genetic part, as you see family forms of MS. Studies have shown parents with MS are more likely to have children who will have MS later. That's what I call genetic predisposition. However, I'm not sure there's an "ethno-genetic" predispsition. As to me, it's very hard to split cultural factors from ethno-genetic factors in studies. But the fact is that some populations are almost free from MS (Japan). But I can't (and no one, I think) say if it's because of environmental or cultural factors or because of genetics.
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Re: Genetic Predisposition

Postby CureOrBust » Mon Sep 17, 2007 3:49 am

Lyon wrote:I... but it now seems obvious that MS incidence is owed to "environmental predisposition" (as the only alternative to "genetic predisposition") and genetic factors, and possibly other environmental factors are secondary "triggers" (only after environmental predisposition could these triggers enable the MS process to begin).

Considering the situation, I don't see how anyone could make a logical argument for genetic predisposition

pre·dis·po·si·tion –noun
1. the fact or condition of being predisposed: a predisposition to think optimistically.
2. Medicine/Medical. tendency to a condition or quality, usually based on the combined effects of genetic and environmental factors.
I think the key word here is "tendency", not a guarantee.
An identical twin of a person who has multiple sclerosis have a 25-percent chance of getting the disease

I don't know if these are the commonly accepted numbers, but a chance of 1 in 4 is damn high. From my understanding, this is really only seen in true identical twins (ie one zygote, same genetics)

A population-based study of multiple sclerosis in twins.
[My paper] G C Ebers , D E Bulman , A D Sadovnick , D W Paty , S Warren , W Hader , T J Murray , T P Seland , P Duquette , T Grey
Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.
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Postby Lyon » Mon Sep 17, 2007 5:35 am

Hi Jean and Cure,
You both make the same point, and a good one regarding higher MS incidence among twins and family members in general...which I called "familial clustering"
tall, dark and handsome wrote:Because of "familial clustering" I am not so foolish as to think that genetics aren't involved in MS incidence
but familial clustering seems to be a secondary issue to the actual predisposition to the disease.

It seems that the facts long ago led researchers to believe that MS incidence requires an essential factor (either genetic or environmental predisposition) and smaller factor(s) (trigger(s), either genetic or environmental) and I can find no reason to disagree with that. Otherwise MS incidence might be owed to a hodge podge mixture of various equal genetic/environmental factors and the odds are just astronomically against that.

I wish I knew more about genetics. The doubts about predisposition possibly not being owed to "ethno-genetics" but maybe some other genetic factor gives something to think about, thanks. I'll look into it.

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Postby TwistedHelix » Mon Sep 17, 2007 11:08 am

I prefer to think of the term " genetically predisposed" in the following way:
Take a typical Scandinavian population. Their genetic makeup will give many of them fair hair and blue eyes, with fair skin. If they are exposed to an environmental risk, (too much sun), there is a greater chance that they will develop skin cancer – but not 100% certainty. This is not the same as saying they have genes " for" skin cancer, or even faulty genes that would lead, on their own, to skin cancer: simply that their genetic makeup makes them more susceptible without actually being faulty in itself.
When it comes to twins and familial links, I think the waters get a bit muddy when you include things like shared environment, upbringing and diet. It's a bit like obese parents who have obese children – most of that will be due to acquired habits like exercise levels and diet but genes might play a part in determining things like height and metabolic rate, so which do you blame as the primary cause of the obesity?
To be honest, I don't think there's a huge semantic gulf between, "predisposed", and, "susceptible" , I think it's quite likely that the MS population might have a perfectly normal variant of the genome but one which, like the fair skinned Scandinavians, leaves us vulnerable to certain environmental circumstances. This variant could be widespread amongst the whole human population but might not show up in certain groups because they have a diet or sunshine exposure which ameliorates the affect of this variation.
Here are a couple of abstracts on the subject, the first is from, the second from in 2005:
Although no specific gene for multiple sclerosis has been identified, several researchers have concluded that people with multiple sclerosis inherit certain regions on individual chromosomes more often than people without multiple sclerosis. Researchers are investigating the human leukocyte antigen (HLA) on chromosome 6, since the HLA patterns of multiple sclerosis patients appear to be different from those who do not have multiple sclerosis. Development of multiple sclerosis is likely to be influenced by the interactions of a number of genes, each of which (individually) has only a modest effect. Additional studies are needed to specifically pinpoint which genes are involved, determine their function, and learn how each gene's interactions with other genes and with the environment make an individual susceptible to multiple sclerosis. In addition to leading to better ways to diagnose multiple sclerosis, such studies should yield clues to the underlying causes of multiple sclerosis and, eventually, to better treatments or a way to prevent the disease.

A cluster of genes on chromosome six is the only one that plays a significant role in multiple sclerosis (MS), according to the most complete genetic study to date in the if disorder, presented at the 130th annual meeting of the American Neurological Association in San Diego.

"Our results confirm the strong role of the major histocompatibility complex genes in MS, and provides a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics," said Jonathan Haines, Ph.D, of Vanderbilt University in Nashville, Tennessee, who presented on behalf of the International Multiple Sclerosis Genetics Consortium.

"A detailed examination of the major histocompatibility complex is critically important," said Haines, who suggests that this study may have profound implications for the future directions of MS genetics research.

The major histocompatibility complex (MHC) is a cluster of genes that play a critical role in the recognition of cells in the body as belonging to the body, i.e., not intruders such as bacteria or other pathogens.

When this system of recognition breaks down, the immune system may mistakenly launch an attack against cells, as happens in MS. Researchers believe that some genetic variations in MHC genes make people more susceptible to whatever environmental causes also contribute to MS.

Haines is one of the founders of an international team of researchers from many institutions that collected genetic data on 730 families with more than one case of MS from Australia, Scandinavia, the United Kingdom, and the United States.

Previous studies have implicated the MHC, but also regions on other chromosomes, as harboring genes that increase MS risk. Haines suggests that these studies failed to include enough subjects.

"This is the largest genetic linkage study on MS, and the first to be done using the latest technology, which provides very detailed coverage of the entire human genome," said Haines. "Other genes may still play an important role in MS, but finding them will require using new genomic techniques."

Multiple sclerosis is an enigmatic disease of the nervous system and results in the loss of myelin, a substance that normally insulates nerve fibers and speeds electrical conduction through the fibers. Patches of inflammation (known as 'plaques') occur throughout the brain and spinal cord resulting in the loss of myelin and sometimes the nerve fibers themselves.

Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission and patients may show little sign of the disease between attacks.


A high density screen for linkage in multiple sclerosis Jonathan L. Haines, Ph.D. (presenting on behalf of the International Multiple Sclerosis Genetics Consortium - IMSGC).
Nashville, TN

This abstract describes the results of what we would consider to be the definitive multiple sclerosis linkage screen. The power of the study is so great that it is virtually certain that all susceptibility loci with effects large enough to be detectable by linkage have been found. The value of a definitive reliable linkage map cannot be overemphasized. The results from this study have profound implications for the future study of the genetics of this complex disorder and enable accurate minimum requirements to be determined for future studies. This is clearly a critical development in the field.

Ten centimorgan microsatellite map have been the standard tool used for whole genome linkage screening since the mid 1990's and to date 11 screens employing this methodology have been published in multiple sclerosis. However the scale and quality of the data in these studies is limited. In order to establish a definitive linkage map we have typed 4506 single nucleotide polymorphism markers in a set of 730 multiplex families from Australia, Scandinavia, the United Kingdom and the United States, which together provide 945 affected relative pairs. Highly significant linkage is observed in the region of the Major Histocompatibility Complex (lod score 11.7) and suggestive linkage is identified on chromosome 17 and 5. Ordered Sub-set analysis identifies a further locus on chromosome 19. The mean information extraction provided by the marker panel is 79.3% (range 42.4 - 91.3%) and the observed Mendelian inconsistencies suggests that within this data set the genotyping error rate is just 0.002%. These data have profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered. In the future association studies will need to include at least 500-1000 cases.

Crystal Weinberger
American Neurological Association
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Postby Lyon » Mon Sep 17, 2007 12:15 pm

Whew! I honestly thought no one would be able to come up with good counter points. I hope no one expects a quick response from me because I'm going back to the books for a while!
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