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Thread: Research article

  1. #1
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    Research article

    Article on genetics vs environment in scoliosis. Just wondering what others think.

    p

    Adolescent idiopathic scoliosis in twins: a population-based survey.
    Andersen MO, Thomsen K, Kyvik KO.
    Spine. 2007 Apr 15;32(8):927-30.
    PMID: 17426641 [PubMed - indexed for MEDLINE]

    Spine Section, Department of Orthopaedic Surgery, University Hospital of Odense, Odense, Denmark.

    STUDY DESIGN: A questionnaire-based identification of adolescent idiopathic scoliosis (AIS) patients in a twin cohort. OBJECTIVE: The purpose of this study was to establish a scoliosis twin cohort to provide data on the heritability of AIS. SUMMARY OF BACKGROUND DATA: The etiology of AIS is still unclear, and the true mode of inheritance has yet to be established. Concordance rates in monozygotic twins have been reported to be between 0.73 and 0.92, and in dizygotic twins between 0.36 and 0.63. Studies on concordance in twin pairs provide a basis for analyzing the influence of genetic versus environmental factors. METHODS: All 46,418 twins registered in the Danish Twin Registry born from 1931 to 1982 were sent a questionnaire, which included questions about scoliosis. A total of 34,944 (75.3%) representing 23,204 pairs returned the questionnaire. RESULTS: A subgroup of 220 subjects considered to have AIS was identified, thus giving a prevalence of 1.05%. The concordant twin pairs were all monozygotic. Pairwise, the concordance rate was 0.13 for monozygotic and zero for dizygotic twin pairs; proband-wise concordance was 0.25 for monozygotic and zero for dizygotic pairs. The concordance of monozygotic and dizygotic pairs was significantly different (P < 0.05). CONCLUSION: We have found evidence for a genetic etiology in AIS, but the risk of developing scoliosis in 1 twin whose other twin has scoliosis is smaller than believed up until now.

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    Interesting abstract.

    As has recently been discussed, there is variation between identical twins in terms of gene copy numbers and epigenetic changes.

    Any study looking at genes versus environment is going to have to account for that inherent variability in their "identical" control subjects.
    Sharon, mother of identical twin girls with scoliosis

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    Quote Originally Posted by Pooka1 View Post
    Any study looking at genes versus environment is going to have to account for that inherent variability in their "identical" control subjects.
    Actually, an genetic study will not be able to address epigenetic changes because those are cell/tissue specific changes. As long as we define scoliosis as ideopathic, then there is no way to test it.

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    Quote Originally Posted by PNUTTRO View Post
    Actually, an genetic study will not be able to address epigenetic changes because those are cell/tissue specific changes. As long as we define scoliosis as ideopathic, then there is no way to test it.
    Right but maybe some day they can at least narrow AIS down to epigenetic changes versus gene copy number let's say without specifying the location of the changes, no?
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

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    Quote Originally Posted by Pooka1 View Post
    Right but maybe some day they can at least narrow AIS down to epigenetic changes versus gene copy number let's say without specifying the location of the changes, no?
    Uh. no.

    In the paper that started this thread, they show a concordance in identical twins to be only 25%. That means that based on genetics alone, there is still a very small contribution by genes to scoliosis--they didn't specify any type for this study. In dizygotic twins--who are as genetically similar as two siblings, but share a more similar environment--there was zero concordance.

    There are other studies that say the contribution of genetics is very high, but this study disputes that.

    "In our opinion, and in accordance with the studies by
    Wynne-Davies8 and Riseborough and Wynne-Davies,9
    the present study supports the assumption that there is a
    significant genetic component in the etiology of AIS. The
    risk of AIS occurring in a monozygotic twin whose other
    twin has the disease is, however, only 25%, and a figure
    substantially lower than that reported in other twin studies."

    p

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    Proband vs Pairwise concordance

    PNUTTRO

    The study found 25% proband concordance but I don't think that's the number you were looking for. Proband concordance is a technical number used for statistical analysis. Pairwise is the number that most people think of when they think of concordance.

    Pairwise concordance was 13%. Put simply if one twin had Scoliosis the other had it just 13% of the time. By comparison if one twin has Sickle Cell disease the other has it 100% of the time. That's what a true genetic disease looks like. This appears to be some sort of weak, genetic susceptability to something in the environment.

    Many twin studies are small or rely on volunteers and this can lead to a poor sample. This study used a large Danish twin registry to avoid both of those problems.
    Last edited by Dingo; 03-25-2009 at 02:09 PM.

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    Dingo! are you a stats person or actuary?

    We could use one here.

    In re the paper, it's interesting that only 13% of the ID twins had a pair-wise concordance. Makes it seem likely that when both twins have scoliosis, it might more likely be due to a connective tissue disorder or some such.

    It would be consistent with the fact that both my ID twins have scoliosis likely due to a connective tissue disorder and not AIS.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

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    Sadly I'm not a statistician

    I only know about this stuff from endless hours of reading.

    Even if both twins have a connective tissue disorder and EVEN IF one of the parents also has the disorder it is still unlikely that it's a true genetic disorder. Although I wouldn't bet my life on it in all likelihood any genes involved merely offer susceptability to something in the environment but don't cause the disease all by themselves. True genetic disorders that hit children tend to be very rare (take a look at these charts). or are specific to certain groups of people. Scoliosis isn't either of those two things.

    Type 1 Diabetes runs in families and if one identical twin has the disorder there is about a 40% chance the other will also have it. It's caused by a common virus called an Enterovirus that hits almost everyone. It's spread through the fecal-oral route and unfortunately it survives in chlorinated pool water.

    Study Of Human Pancreases Links Virus To Cause Of Type 1 Diabetes

    In all likelihood Scoliosis works something like that. Our children have a genetic susceptability and they ran into a microbe that damaged something in their bodies.
    Last edited by Dingo; 03-25-2009 at 05:06 PM.

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    Quote Originally Posted by Dingo View Post
    I only know about this stuff from endless hours of reading.
    In that case, I'm *very* much looking forward to PNUTTRO's reply <grin>.

    I see from your signup date that you haven't been around here long enough to really have a vague idea what P does (hint ... I've been stuck at the hospital with my Mom the last few days, and P's brief escapes from the research lab to visit have been most welcome).

    This should be interesting, although admittedly, I'm bored - LOL.

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    Quote Originally Posted by Dingo View Post
    I only know about this stuff from endless hours of reading.
    Damn.

    Even if both twins have a connective tissue disorder and EVEN IF one of the parents also has the disorder it is still unlikely that it's a true genetic disorder. Although I wouldn't bet my life on it in all likelihood any genes involved merely offer susceptibility to something in the environment but don't cause the disease all by themselves. True genetic disorders that hit children tend to be very rare (take a look at these charts). or are specific to certain groups of people. Scoliosis isn't either of those two things.
    Marfans, for example, is known to be genetic if I am understanding this stuff. Moreover they know that ~25% of Marfans cases are spontaneous (genetic) mutations. Now don't ask me how they know it is a spontaneous mutation and not some viral challenge plus a susceptibility because I am not a bio research type. Here's where we need Pnuttro.

    Type 1 Diabetes runs in families and if one identical twin has the disorder there is about a 40% chance the other will also have it. It's caused by a common virus called an Enterovirus that hits almost everyone. It's spread through the fecal-oral route and unfortunately it survives in chlorinated pool water.
    I don't think Type I runs in families. My brother is the only person on either side of my extended family who has Type I. Also, my post doc adviser was the only person in his extended family with Type I. This is only two people but I never heard Type I runs in families ever. It has been thought to be a virus for along time, even back when my brother was diagnosed in 1990.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
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    Type 1 doesn't hit everyone

    Pooka1

    Type 1 doesn't hit everyone in a family but if you have a 1st degree relative with Diabetes you are more likely to get it.

    BTW, that doesn't automatically mean genetics. If you and your brother both frequent a pool that is contaminated with Enterovirus you might both get Diabetes and it has nothing to do with genes.

    Type 1 diabetes tends to run in families
    Brothers and sisters of children with type 1 diabetes have about a 10 percent chance of developing the disease by age 50.

    The identical twin of a person with type 1 diabetes has a 25 to 50 percent chance of developing type 1 diabetes.

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    Quote Originally Posted by Dingo View Post
    Pooka1

    Type 1 doesn't hit everyone in a family
    You're not kidding. In my two examples it only hit ONE person among the immediate and extended families... hundreds of people.

    but if you have a 1st degree relative with Diabetes you are more likely to get it.
    Not convinced at this point. I would have to see the data. BTW, did you realize most published research results are false?

    BTW, that doesn't automatically mean genetics. If you and your brother both frequent a pool that is contaminated with Enterovirus you might both get Diabetes and it has nothing to do with genes.
    Right. My brother is only 11 months older. We were like twins and did everything together for years. We frequented the same pools as a rule and at the same time. He developed Type I at 30 (as did my post doc adviser by coincidence). At that point, we weren't frequenting the same pools and such. It seems that a mis-targeted immune response to a bacterial or viral challenge is likely.

    Type 1 diabetes tends to run in families
    Brothers and sisters of children with type 1 diabetes have about a 10 percent chance of developing the disease by age 50.

    The identical twin of a person with type 1 diabetes has a 25 to 50 percent chance of developing type 1 diabetes.
    Not convinced. I question that. I would like to see the underlying data for that.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
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    "We are all African."

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    You can't absolutely trust any single study but...

    BTW, did you realize most published research results are false?

    You are right, you can't absolutely trust any single study. That's why scientists do dozens of studies to answer just one question. I don't have any Diabetics in my family so I don't follow it very closely. However it's an old disease and I would assume that by now hundreds of studies have been done on Diabetes and heredity.

    American Diabetes Association
    In most cases of type 1 diabetes, people need to inherit risk factors from both parents.


    "In most cases of type 1 diabetes, people need to inherit risk factors from both parents. We think these factors must be more common in whites because whites have the highest rate of type 1 diabetes. Because most people who are at risk do not get diabetes, researchers want to find out what the environmental triggers are."

    Of course none of that means that any part of Diabetes is actually genetic. It's just that genes make people susceptible to the environmental trigger that causes Diabetes which now appears to be the Enterovirus.

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    Quote Originally Posted by txmarinemom View Post
    In that case, I'm *very* much looking forward to PNUTTRO's reply
    Sorry, Pam. Aside from clarifying the proband concordance vs the pairwise concordance, I am at a loss as to what I should be responding to.

    Most genetics studies are done using proband ascertainment because as Dingo points out, most genetic diseases are rare. Dingo is right the authors here tried to aviod this bias.

    "The pairwise concordance (Pp) is the proportion of affected twin pairs in which both members are affected, so this concordance estimates the probability that both twins are affected in a pair in which 1 is affected." (6/44 pairs)

    "The proband-wise concordance (Ppr) is defined as the proportion of co-twins with the trait for individuals independently ascertained, so the proband-wise concordance estimates the probability that a twin will be affected given that the twin partner is [affected]." (In this case, 2*6/44 individuals)


    The article that I referenced in this thread was a very good genetic study that, I think, has a simple take home message. A person's risk of acquiring scoliosis is determined more by one's environment rather than genetics. (25% contribution of genes if you are a proband concondance person or 13% if you are a pairwise concordance person). Other studies that are referenced in this paper say there is a much higher contribution by genes. The authors claim that this may be an ascertainment bias.

    Because Sharons twins both have scoliosis, it is likely their genetic contribution to scoliosis is greater than that of most individuals in the population.

    The trouble with genetics is that predictions are based on a risk assessment, but a high genetic risk doesn't mean that you will acquire any condition. Its only a probability.

    I don't know where the Type I diabetes stuff came from. I think its a bit of a stretch to say that a virus or other pathogen causes scoliosis--unless someone can dig that paper out of the abyss.

    It begs the question, if 100, 10 year old boys are in a swimming pool and one of them poops, which releases enterovirus into the pool, and we assume that the virus is evenly distrubuted throughout the water. How many people will acquire Diabetes at 30 years of age? Will they all be related?

    p

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    Virus causes Scoliosis?

    PNUTTRO

    I have no evidence that a microbe causes Scoliosis. So far I don't think anyone has ever looked or even knew where to look.

    However your twin study strongly suggests that Scoliosis is triggered by the environment. So what could that be?

    A) Scoliosis existed long before pollution
    B) It existed long before food additives and pesticides
    C) It existed long before modern medicine or vaccines
    D) It existed long before kids sat in front of TVs and computers

    So what's left that can damage or alter the central nervous system and screw up cAMP levels?
    The only idea I can come up with that makes any sense is a pathogen.

    If that's how this turns out remember that Dingo said so years earlier.
    Last edited by Dingo; 03-28-2009 at 11:56 PM.

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