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PNUTTRO
03-02-2009, 04:43 PM
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.

Pooka1
03-04-2009, 11:07 AM
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.

PNUTTRO
03-04-2009, 11:30 AM
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.

Pooka1
03-04-2009, 11:48 AM
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?

PNUTTRO
03-04-2009, 02:24 PM
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

Dingo
03-25-2009, 01:49 PM
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.

Pooka1
03-25-2009, 03:28 PM
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.

Dingo
03-25-2009, 04:53 PM
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) (http://en.wikipedia.org/wiki/Genetic_disorders). or are specific to certain groups of people. Scoliosis isn't either of those two things.

Type 1 Diabetes (http://en.wikipedia.org/wiki/Diabetes_mellitus_type_1) 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 (http://en.wikipedia.org/wiki/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 (http://www.sciencedaily.com/releases/2009/03/090305141639.htm)

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.

txmarinemom
03-25-2009, 05:36 PM
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.

Regards,
Pam

Pooka1
03-25-2009, 05:49 PM
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) (http://en.wikipedia.org/wiki/Genetic_disorders). 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. :D


Type 1 Diabetes (http://en.wikipedia.org/wiki/Diabetes_mellitus_type_1) 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 (http://en.wikipedia.org/wiki/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.

Dingo
03-25-2009, 09:08 PM
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 (http://www.chw.org/display/PPF/DocID/22658/router.asp)
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.

Pooka1
03-26-2009, 06:28 AM
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 (http://www.chw.org/display/PPF/DocID/22658/router.asp)
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.

Dingo
03-26-2009, 01:29 PM
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. (http://www.diabetes.org/genetics.jsp)

"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.

PNUTTRO
03-27-2009, 04:10 PM
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

Dingo
03-28-2009, 11:51 PM
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 (http://pico.sssup.it/files/allegati/2004_1469.pdf)?
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. :)

titaniumed
03-29-2009, 02:16 AM
Yup.

Well, we know pollution does not help at all.

Ok, how about gravity? Thats been around for a while! Gravitational effects on the brain?

Hard to prove with gravity everywhere.

Oh well,just an idea.

Magnetism is another thought.

Ed

concerned dad
03-29-2009, 07:52 AM
Gravity?
Magnetism?

Finally something I actually know about.

Damn, nothing to add.
:D

PNUTTRO
03-29-2009, 08:13 AM
In genetics studies, anything not attributable to inheritance, is environment. And consequently, not easily studied.

It could be:
diet
stress
epigenetics (thank you Sharon)
Doing a repetitive movement or no movement
muscle weakness
Cell signaling
post-translational modification of proteins
hormone regulation
etc


So what's left that can damage or alter the central nervous system and screw up cAMP levels?

Who says that my CNS is jacked up? Your referenced paper is about melatonin signaling pathways in bone.

Pooka1
03-29-2009, 08:48 AM
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 (http://pico.sssup.it/files/allegati/2004_1469.pdf)?
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. :)

Well, until someone disproves it, you might be right.

And I might add about all this microbes causing diseases business, small pox killing 500 million people (including many children) in the 20th century, etc.... that's some fancy "intelligent" design. :cool:

Pooka1
03-29-2009, 09:00 AM
Well, we know pollution does not help at all.

No actually the thought w.r.t. Type I diabetes is that we have cleaned up our microenvironment so much that the lack of immune challenge from microbes, dirt, etc. may lead to an inappropriate huge response that triggers autoimmune damage.

We should be eating more dirt. As I understand it. :)

Now you are of course correct w.r.t. xenobiotic compounds as opposed to natural microbes and dirt and such.

Then there is stuff that comes out of the blue... Tasmanian devils are headed towards extinction from clonal tumors.

http://www.nytimes.com/2008/11/18/science/18devil.html?pagewanted=1&_r=1

Hopefully the guys working on saving them succeed.

Dingo
03-30-2009, 09:55 AM
PNUTTRO

Who says that my CNS is jacked up? Your referenced paper is about melatonin signaling pathways in bone.

Unless I'm confused (always possible) Melatonin signaling (http://www.google.com/search?hl=en&q=melatonin+signaling+central+nervous+system&btnG=Search) is managed by the Central Nervous System.

When my 5 year old was diagnosed with a 10 degree curve I asked his doctor what caused Scoliosis. He told me that his friends in the research community believed it was a neurological disorder. The crooked spine we see is the side effect. My son is smart, happy, athletic, handsome, etc. etc. So clearly it is a very focused type of damage. I assume that the cells or neurons responsible for Melatonin Signaling are either dead or damaged. It reminded me of Diabetes where a virus leads to the destruction of just one type of cell and leaves everything else intact. Regardless of the cause if the 13% pairwise concordance holds up it's clearly environmental damage of some type. I doubt gravity will be on the short list for disrupting Melatonin Signaling. 8-)

Dingo
03-30-2009, 10:06 AM
Pooka1

Wow, that's too bad about the Devils. A lot of cancer in humans are now blamed on various pathogens.

Depending on the article I read scientists now believe that anywhere from 15% to 20% of cancers are caused by microbes. Just a couple of decades ago scientists didn't think that any common cancers were caused by microbes. That's a pretty big shift.

Boston Globe: Contagious Cancers (http://www.boston.com/news/health/articles/2007/11/12/contagious_cancers/)

PNUTTRO
03-30-2009, 03:04 PM
Now, we get to the heart of the matter.

This whole discussion is not about melatonin, tamoxifen, pathogens or genetics. Your motivation here is regarding your son. I think if you keep that foremost in your thoughts, you will find the best treatment option (or not treatment option) that is appropriate for you and your family.

I will try to summarize what little I know about melatonin and all that you related here. First, melatonin is a hormone produced in the pineal gland and circulates in the body via the blood stream. As far as I know, there have been no studies that say that there is a failure to produce melatonin in people with scoliosis. There is, however, some reason to believe that there is some relationship between genetic variations in melatonin and the way bone cells of scoliosis patients respond to it.

cAMP is a second messenger (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=second%20messenger,cAMP&rid=mcb.section.5717#5732). In the study you posted, it is used as a mechanism by which the scientists can detect signaling within the cell as a result treatment with melatonin. It is NOT a diagnostic measurement. These studies are interesting for understanding the biology of osteoblasts, but have no diagnostic value.

Regarding the tamoxifen issue, these authors really do seem to think the a highly toxic drug seems appropriate for the treatment of scoliosis. They don't state it outright, but they offer no alternative either, such as, this is an interesting biological study. I hate to dismiss it outright without reading it all the way thru, but the premise is so unpalatable to me.

You can read my other posts about genetic testing for scoliosis. Dr. Ogilvie is at Axial Biotech--enough said. Dr. Moreau had a press conference several years ago about how he was going to cure scoliosis. I have no time to entertain such thoughts until a treatment is offered. Genetic testing is not a treatment and will likely not change the course of anyone's scoliosis treatment at this time or any time in the near future.

Meanwhile, if melatonin is the at the root of the problem, maybe exposure to the sun in the daytime and a regular sleep schedule is appropriate.

PNUTTRO
03-30-2009, 03:40 PM
My comments regarding tamoxifen in the previous post referred to the mouse paper (http://www.ncbi.nlm.nih.gov/pubmed/19242737?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) by Turkish authors. In the chicken model (http://www.ncbi.nlm.nih.gov/pubmed/19282733?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum), the authors clearly state that they used tamoxifen just to look at biology.

Quotation from chicken paper:
"Calmodulin is known to be the second messenger for melatonin on various target tissues, probably including striated muscle as well. Melatonin may have an effect on the spinal alignment by way of modulating the paraspinal muscle tone presumably by way of the anticalmodulin effect."

Pooka1
03-30-2009, 04:27 PM
I just hope PETA doesn't find out about the "bipedal" mice and how they get that way. :eek:

And do they really walk around on their hind legs or do they drag themselves backwards or something? Either way, I don't see how that is relevant to a true bipedal animal (humans). They might as well leave them quadrupeds as far as I can tell.

concerned dad
04-08-2009, 07:48 PM
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.

OK, now I am confused.

Just exactly on what point do you disagree with Dingo?

I thought I remembered reading where you said what I quoted above. Now after rereading it, it looks to me like you agree.

Maybe I am being dense and you disagree with the WAY he said it rather than WHAT he said.