Advanced Maternal Age Associated with AIS?

[hdugger]

BTW, your "more genetic" "less genetic" makes sense. As it's commonly understood, a genetic condition is the thing that makes the disease occur/progress. Although there must also be genes underlying the normal condition, noone ever talks about it that way.

Noone ever talks about people *without* heart disease having a genetic condition. It's just assumed that their genes are correct, and the ones that make heart disease more likely are incorrect (and, thus, genetic).

I understand that's not the hard, scientific definition, but it's the usage that makes sense in an informal discussion.

[Dingo]

Skevimc

Actually I'm also interested in what the people on the environment side of the argument see the role that genetics plays in the eitiology and progression.

Because nobody is sure how Scoliosis develops I choose to bet on what scientists know about other relatively common diseases that strike young people.

The three disorders that come to mind are Narcolepsy, Multiple Sclerosis and Diabetes. The initiating mechanism for all three is thought to be the same. An environmental insult strikes someone who posesses a genetic susceptability.

Immune fault 'link' to narcolepsy

Dr Mignot said: "Narcolepsy is probably the result of a series of unfortunate events, starting with genetic predisposition, involvement of an environmental trigger such as an infection, then T-cell activation, then effects on many other arms of the immune system."

Further Evidence Links Epstein-Barr Virus and Risk of Multiple Sclerosis

MS is a chronic degenerative disease of the central nervous system. Women are more likely than men to get the disease and it is the most common neurologically disabling disease in young adults. Although genetic predisposition plays an important role in determining susceptibility, past studies have shown that environmental factors are equally important.

Viral Infection Linked to Juvenile Diabetes

Type 1 diabetes develops in individuals who are genetically susceptible. An exposure to some yet unknown triggering environmental factor or factors may be required.

In the case of MS genes may play a role in the severity of symptoms.
Gene Variant May Increase Severity of Multiple Sclerosis

While the OAS1 gene was weakly associated with disease susceptibility, the study found that people who had the AA genotype had earlier relapses and increased disease activity compared to those without the genotype

I assume Scoliscore is finding genes that aren't so different from what was found in the MS study. Certain genes may slightly increase disease susceptability but significantly increase the severity of symptoms. The "curve progression genes" that Scoliosis detects are probably beneficial in healthy individuals. They don't become a problem until the body is damaged and Scoliosis is set in motion.

[Pooka1]

OK. I see your point. As far as actual function of the genes are concerned, no, nothing is known about the role they play in scoliosis progression. It's based solely on a regression formula. So in a sense, it's not all genetics, it's really just statistics. Because correlation does not equal causation.

That's a good point about this being stats. Good stats but still stats.

But seriously... In the list of genes they used for the formula they do have an indication of what they say is protective and non-protective (I forget the actual words they used). I couldn't find anything written as to how they determined that. Since everything was based mostly on the regression equation, I'd imagine the values were based on the coefficient. So if something was negatively correlated they termed it 'protective' and if something was positively correlated it was causative or whatever they used. (I'll look it up later).

I still haven't read the paper but I suspected they found both "protective" and "causative" genes (all just correlatively) just because they were throwing such a wide net. And they caught such a huge number of fish that they may never get beyond correlation from this approach. That said, the correlation is pretty damn tight so they may not have to in order to predict with a high degree of accuracy.

The idea that the genes postively AND negatively regulate the curve is certainly a hypothesis. Although I can't imagine being able to actually test that. To test the complex interplay of 53 genes and 6 or 8 gene to gene interactions with enough power to confirm the positive and negative regulators would be exceedingly difficult (to put it mildly). Especially when adding in the extra layer of which genes are actually being coded into usable proteins. Regardless, I do see how what you're suggesting is possible but I think it's probably one of those "how many birds are in flight at any given moment" kind of things.

As long at the correlation is tight, this is not necessary.

Let me ask, what role do you see the environment, defined however, playing in etiology and progression?

Well first I was blindsided at the idea that incidence and progression are not controlled by the same gene suite. I find that counter-intuitive but of course I'm a molecular type but not a DNA molecular type. Given the strong inheritance patterns noted, I would say if it is an environmental trigger, it is ubiquitous both in space and time. If so, it might explain why the researchers are all pursuing hypotheses that are genetic-based. It might not be just the best hope but the only hope of finding the etiology.

Last, I was also blindsided by the resistance to the idea that a disease is genetic. I'll bet every person infected with HIV wishes that disease was genetic and not straight germ theory. I don't understand what drives the thinking on that and other things.

I'm blindsided a lot I guess. That's because I'm a bunny in this field.

[Pooka1]

I am very happy to accept the environmental role exactly as the experts in this field define it. So in effect, they are all doing either straight genetics as in Scoliscore or secondary genetics such are biochemical signaling pathways, hormone agonists, whatever... not my field. It seems like all those guys think genetics (straight or secondary) is the best hope and who am I to question that? Their field, not mine.

I will toss out the following... can anyone find even a single paper on someone working on environmental etiology in the lay sense to mean straight germ theory?

Assuming there is an environmental trigger in the straight germ theory sense as such and that it is ubiquitous in space and time, what could it be at that point?

Whenever this discussion comes up I often think of the movie, "Andromeda Strain" wherein the cure was simply to expose the bacteria to oxygen or something like that. If I am remembering that correctly, ridiculous as it would have died before infecting all those people but never mind.

So I suppose certain bacteria might be mostly ubiquitous in space and time but I don't know that. UV radiation is ubiquitous in time (for our purposes here at least) but not ubiquitous in space.

It's not going to be a 20th century pollutant because of the constancy of the worldwide incidence.

Maybe it's a prion in which case I suggest it is intractable and you have to work with the effects.

Maybe it's people praying or praying too much. I have evidence that no prayer whatsoever has worked in some serious cases in my family.

Who knows.

[hdugger]

Last, I was also blindsided by the resistance to the idea that a disease is genetic. I'll bet every person infected with HIV wishes that disease was genetic and not straight germ theory. I don't understand what drives the thinking on that and other things.

- "Resistance" implies that there is a wide consensus amongst experts that the incidence and progression of scoliosis is completely genetically determined, and people are holding out or resisting accepting that idea. In fact, no such wide consensus exists, and thus noone can resist - they can only disagree with one of many ideas proposed.

- The view being disagreed with is not that scoliosis has a genetic component, but that it is entirely genetically predetermined from start to finish, and so strongly predetermined that the spine will always return to where it was genetically predetermined to be no matter what intervention is tried and no matter what the conditions in the environment. The genetic view being *agreed*with is the mainstream view that scoliosis is multifactorial (a combination of genetic predisposition and environment).

- I can't parse the statement on HIV at all. Is the idea that people who already *have* HIV would like to believe that their behavior had nothing to do with getting it? If so, yes, it is emotionally difficult to know that something I did or failed to do is causing my child to suffer. Emotionally difficult doesn't begin to describe it. But, my emotional comfort isn't the point. The point is to figure out how to stop or decrease his suffering. I can't help him by protecting myself with the idea that he's just the victim of a genetic "fate."

[Pooka1]

- The view being disagreed with is not that scoliosis has a genetic component,

Disagree.

but that it is entirely genetically predetermined from start to finish,

This is the consensus of the experts per that recent "top theories" talk.

and so strongly predetermined that the spine will always return to where it was genetically predetermined to be no matter what intervention is tried and no matter what the conditions in the environment.

I doubt any expert says this as it doesn't follow logically from the predicate. This is folk science.

- I can't parse the statement on HIV at all.

The point is that the folk science consensus appears to be that straight germ theory is somehow intrinsically more tractable in terms of treatment than is a genetic etiology. That is clearly not the case for HIV which continues to resist the finding of a vaccine. If an effective vaccine existed these folks wouldn't have become infected.

[skevimc]

If so, yes, it is emotionally difficult to know that something I did or failed to do is causing my child to suffer. Emotionally difficult doesn't begin to describe it. But, my emotional comfort isn't the point. The point is to figure out how to stop or decrease his suffering. I can't help him by protecting myself with the idea that he's just the victim of a genetic "fate."

This actually brings up one thing I wanted to say about the original reason for this thread. I read through the advanced maternal age papers. And while it seems to carry a bit of consistency through several different studies, it seems more like an anomaly or weird coincidence in the data. If there is actually something to it, the wide range of time and different countries in which the studies were done would make it nearly impossible to make a suggestion as to why advanced maternal age would do anything to affect the curve. I'll also say that the differences in age in the studies is pretty small. The study that compared 'scoliosis mothers' to the general population had an age difference of less than 1 year. Something like 27.5 versus 28.3. It would be pretty difficult to say that extra .8 years was the deciding factor.

Anyway, the point I would want to make is that studies like these are frustrating because I think parents are probably already wondering if they did something wrong. And this just adds unecessary fuel to what ever fire might be burning there. I know from my own medical history that if my daughter ends up with a similar history as mine I'll be pretty bummed about it. To the T-Rex in Toy Story "Great! Now I have guilt too!"

[hdugger]

Actually, I sort of forgot what thread I was in No, it wasn't the maternal age that concerned me. My role in being too old and passing on crummy genes doesn't actually bother me. That just seems like a roll of the dice.

The things which do concern me is stuff that I considered as not-so-great for him but not important enough to become the big battles in his late teen years (when there are so many more seemingly important battles to fight). Things like sleeping in and getting too little sunshine, or spending way too much time at an oddly configured computer desk where he had to reach up with his mousing hand. My heart really sank when, the first time my very savvy masseuse (the person I credit with addressing alot of his cosmetic and alignment issues) saw him walk though the door she asked him "Do you spend alot of time on the computer?"

I understand that he was already at risk to progress, given his body type, but I suspect some combination of his genetic predisposition and the environmental triggers is what threw him over the edge.

I'm not all that prone to wallowing - mostly I worry more about the future then the past - but in trying to address what I can do now to make things better, I become more aware of what I might have done to make things worse. The discomfort of that guilt pales in comparison to what he's going through. I only bring it up to address the idea that it would make more emotional sense to blame it all on the genes. That would be an easy out for me, but not one that serves my son well.

[Pooka1]

There is no blame in biology.

It simply is what it is.

[Pooka1]

No evidence WHATSOEVER

There is no evidence whatsoever that sitting at a computer, not sitting at a computer, getting a lot of sunshine, not getting a lot of sunshine, etc., not etc., affects any curve at all in any way. If they can't even cleanly show that bracing and PT affect a damn thing then how can they ever show these other things? One can't just "feel" these things matter. Feeling and not proffering evidence is the ambit of folk science.

I suggest it is futile and wrong to beat oneself up over any such thing.

This is biology. A science. Only evidence moves the needle.

ps. Are we on Candid Camera???? What is with resisting science? I don't get it.

[Pooka1]

The idea that the genes postively AND negatively regulate the curve is certainly a hypothesis. Although I can't imagine being able to actually test that.

I was thinking about this. The fact that Scoliscore is far stronger with negative prediction (i.e., a curve won't >40*) as opposed to a positive prediction (a curve will be greater than 40*) might imply that they are measuring largely protective genes (or their correlates).

So there could be far more genes involved in "mild" cases compared to "severe" cases though that doesn't mean smaller curves are more genetic than larger curves.

[Ballet Mom]

Assuming there is an environmental trigger in the straight germ theory sense as such and that it is ubiquitous in space and time, what could it be at that point?

Chickenpox. It infects most people prior to their adolescent growth spurt and has been around forever. The varicella-zoster virus is known to lay dormant in the spinal ganglia and cause shingles later on when it reactivates.

It's really too bad they decided to use a live virus for a vaccine instead of a killed virus. It seems to me we would know at this point if the varicella-zoster virus had any kind of effect on scoliosis if they had. Instead, they now have to give large dose vaccines for shingles to older people, and two chickenpox vaccines to others.

[Ballet Mom]

Anyway, the point I would want to make is that studies like these are frustrating because I think parents are probably already wondering if they did something wrong. And this just adds unecessary fuel to what ever fire might be burning there. I know from my own medical history that if my daughter ends up with a similar history as mine I'll be pretty bummed about it. To the T-Rex in Toy Story "Great! Now I have guilt too!"

Lol on T-Tex. Having guilt might be a natural reaction but it is completely irrational. What could anyone do about this other than persuade our society to have kids at a younger age than they have in the past thirty years. I know I will be telling my kids to have their children younger, because it seems like the odds increase for many bad things to happen when you have babies older, including just not having the energy to deal with those young bundles of joy.

I had a boss years ago who had her children when she was eighteen + and went to college part-time while raising them, then when her kids were a lot older she went back to work without having to deal with all the sick kids and childhood demands, etc. and then was managing all of us in a hugely responsible position and promoted to the top executive of our organization during my tenure there. I, of course, after getting all my education and working for sometime was having babies and dealing with all their childhood illnesses and needs at the peak time when people are being promoted to executive level positions. Which path was probably the better? I think as a society, we can probably do better.

[Pooka1]

Which path is better?

Many factors but one deals with actually leaving the starting gate...

I can say that in my cohort of PhD students, of the few who never finished, most (not all) of those had kids.

[Ballet Mom]

This actually brings up one thing I wanted to say about the original reason for this thread. I read through the advanced maternal age papers. And while it seems to carry a bit of consistency through several different studies, it seems more like an anomaly or weird coincidence in the data. If there is actually something to it, the wide range of time and different countries in which the studies were done would make it nearly impossible to make a suggestion as to why advanced maternal age would do anything to affect the curve. I'll also say that the differences in age in the studies is pretty small. The study that compared 'scoliosis mothers' to the general population had an age difference of less than 1 year. Something like 27.5 versus 28.3. It would be pretty difficult to say that extra .8 years was the deciding factor.

I actually think this is quite an interesting line of thought. My daughter's great-grandfather whose sister had a severe case of scoliosis was a thirteen pound baby! The odds are that his sister was also a very large baby. Did she have some kind of trauma and damage during delivery that could have caused the scoliosis during later growth increased by the fact that they have the double-jointedness gene?

My son was born at 9 lbs 8 oz. The OB/GYN thought he'd just delivered a UCLA football player. The nurses who would come into my room would exclaim they couldn't believe I was the one who had the big baby...because I wasn't big or overweight. My daughter was induced two weeks early to try and keep her size down due to her brother's weight. She turned out to be 8 1/2 pounds anyway. I did not have increased weight or gestational diabetes, am not black, and did not have any of the things that typically increase the size of newborns. We just have big babies, I guess. Funny thing, neither of my kids actually ended up big. No football players in my family!

And big babies are known to increase with age due to higher maternal weight and gestational diabeties which increase around the age of thirty. Sounds familiar with the studies, doesn't it? And now scoliosis is decreasing, and use of forceps is decreasing and c-sections are increasing.

It's just kind of interesting that scoliosis shows up at a higher rate in athletes, especially ballet, gymnastics and swimming, I believe. So maybe this possible birth trauma could cause the scoliosis with the repetitive motions in these intense activities and take-off during the adolescent growth spurt.

I hardly think it's something to just write off. There may be something to it for an enterprising researcher.