Understanding Genetic Associations

[gfb1]

i have been discouraged by the tendency of the medical community to 'name' HLA DQ haplotypes as being 'celiac genes'. unfortunately, the celiac community seems to have adopted the misnomer, and seems to have embraced genetic testing. lets be clear; the HLA genes are not celiac genes. they are immune-related genes that have also been associated with other diseases, ranging from myasthenia gravis to graves disease to type 1 diabetes.

genetic association studies have come a long way since animal breeders (mistakenly) thought that brown hair color was associated with high milk production in dairy cattle (guernsey's take THAT). genetic markers have developed from simple physical characteristics to specific protein and DNA sequences. statistical techniques have improved from anecdotal evidence to precise mathematical models. but make no mistake; regardless of precision - the ACCURACY of such models is still subject to the same faults as the original association paradigm.

you can see the logical error -- sticking with our bovine example:

brown cows give more milk than black/white cows.

all brown cows are better milkers than all black/white cows.

if you want more milk, get rid of all black/white cows.

curiously, a recent paper in Open Original Shared Link has been published finally comparing the use of genetic markers with non-genetic predictors of various diseases (in humans; not cows). unsurprisingly, having data on 9-12 genetic markers were NOT better predictors of disease status than the non-genetic factors.

Not only are risk results likely to be often poorly understood by the tested individuals and their physicians, but also these results are often based on risk models, such as logistic regression models, that may not be good classification models. Therefore, the disclaimer made by the companies that their services are not intended as medical advice cannot be overemphasized.

this cautionary disclaimer is critical and (imho) needs to be thoroughly understood by anyone who decides to be tested. tested individuals desperately need solid advice from a professionally trained geneticist -- not a medical doctor, nutritionist (and don't get me started on that -- see an RD for pete's sake), or representative of a testing laboratory. please consult a professional whose last genetics course (IF there was one) was taken more recently than their freshman biology class.

i really believe that all the fuss about markers (in this case the HLA DQ haplotypes) feeds the desire of a class of sick and pained people - -who have been consistently misdiagnosed, mist-treated (in the medical sense) and ignored-- to have a 'test'. to 'prove' their disease is real and to exert some level of control over the expression of the disease in future generations.

it has also served to eliminate or, at least, soften the clamor for research designed to identify the actual gene for celiac disease (if it is, indeed,, a simply inherited trait), or to identify the mode of inheritance and expression of the disease, which would provide guidance to celiacs who either have, or are planning to have, children.

[Mother of Jibril]

If you stick around on this forum and do some reading, you'll find that a lot of people here are actually VERY concerned about the reliability of genetic testing, which genes are considered (or not considered) the "celiac genes," how these genes are triggered, the relationships between celiac and other autoimmune disorders, etc...

What is your interest in genetics? Have you seen it used or misused in specific ways and you're reacting against that? You make a lot of bold statements that seem unwarranted to me.

[nora-n]

We also had some mistyped people here, who turned out to have DQ8 or something anyway, and we have only heard from one person with half the gene.

according to pubmed 68 of 1008 european celiacs have half the gene, and 0,4% have other genes thatn DQ2 or DQ8.

(they have done models of the antigen receptors and DQ2 and 8 form a shape where giadin or whatever can lock in. Dq7 and DQ9 bind gluten weaker)

Maybe many of thse with other genes here really are mistyped??

And, several DQ2,2 are here, maybe they are DQ2,5 in trans but the lab did not report the missing alpha chain. Maybe.

nora

[gfb1]

for better or for worse, i've been a geneticist for the greater part of my adult life -- with a career spanning a variety of experiences ranging from working in industry, teaching genetics (for 20 yrs) to chairing the graduate program in genetics at a major university. my graduate students have landed in jobs ranging from medical schools to vet schools to industry to dna crime labs. i have taken early retirement from the university to start a biotech company -- which has given me some 'leisure time' to jot some notes in places that i have had long-standing interests.

my wife was diagnosed with celiac at johns hopkins by the (then) director of hepatology in the early 90's -- after a 5-6 yr series of misdiagnoses: ranging from irrritable bowel, et al. to psychosomatic to (ultimately) autoimmune hepatitis. luckily, the doctor had recently been to a seminar in spain -- where there was a single clinical report of a patient exhibiting hepatitis symptoms, but had celiac disease. i believe my wife is written up in jama in 94/95; but, i couldn't finagle co-authorship -- so i lost track...

she is well and has been gluten-free for over 15 yrs and haven't looked back -- although she remains a stalwart resource for friends and community regarding celiac disease (and has taught community ed classes on cooking gluten-free over the years).

my wife's family was one of the early families to join dr.fasano's 'old' study. dr. fasano has written some elegant posts in this forum (some of the best of the bunch, and should be read/re-read by everybody). through sheer force of will my wife has gotten all of her nuclear family (5 sibs & her dad), their spouses and children, and the occasional aunt/uncle/cousin to be blood-tested and biopsied for celiac disease. i follow the scientific literature quite closely, and i maintain that she has the single largest pedigreed family (ca 35 individuals) , with appropriate testing, ever reported.

while some of my statements may seem bold, i'm not sure which are incorrect. genes of the major histocompatability locus are NOT celiac genes, per se. they may modulate immune response to particular antigens; one of which *may* be gluten-related (and this has NOT been proven) -- but, they do NOT cause the disease (there have been a handful of posts that address this point as well).

i also feel that there are a lot of companies making fairly significant $$$ off of vague promises to 'genotype' individuals and identify 'genes' for a variety of diseases. mostly, these are crap. there are many clinically relevant and important genes that cause diseases among families and there are 'tried&true' genetic tests for them. unfortunately, celiac disease is not one of them (then again, neither are many of the terrible diseases that afflict humankind).

[gfb1]

jeez. that post was ridiculously long and long-winded.

i still write like a damned academic.

sorry.

[Lisa]

i also feel that there are a lot of companies making fairly significant $$$ off of vague promises to 'genotype' individuals and identify 'genes' for a variety of diseases. mostly, these are crap. there are many clinically relevant and important genes that cause diseases among families and there are 'tried&true' genetic tests for them. unfortunately, celiac disease is not one of them (then again, neither are many of the terrible diseases that afflict humankind).

gfb1,

Welcome to the Forum! I have enjoyed all of your recent postings. It's refreshing to find "fresh" information here.

I am most interested in this quote, as it confirms my undocumented assumptions. I warn you though, you may generate some emotional responses. One of these companies, that you noted, has a very loyal clientele.

Once, again welcome.

[lbd]

gfb1,

I feel part of the problem is that some people like to think of celiac as a disease rather than a response to an environmental toxin. It is not the genes that cause the "disease" rather it is the lack of genes enabling one to process gluten grains correctly that can lead to physiological changes in the body that lead to disorders. The genetic factor comes into play when an individual does not have the genetic makeup to handle the toxin properly. In other words, having a certain genotype predisposes one to a response to gluten (either immune or autoimmune), and does not cause the response. The severity of the response, either immune or autoimmune, may depend on the genotype and the exposure to the environmental factor, in this case, gluten.

I think the problems with gluten are becoming more obvious as the diets in our society become more and more loaded with grains.

So, I don't think genetic testing in relation to celiac or gluten sensitivity is crap. I do believe it can indicate a predisposition, and if one has actual responses to gluten, then one can take measures to remove the toxin from the diet.

Laurie

[Lisa16]

Hi gfb1. I have a question for you.

Many of the people who get tested here do so through Enterolab. You will see many posts here regarding this company-- both positive and negative. If you read the fine print of the Enterolab genotyping results, they say they send their samples to the American Red Cross for typing. They do the other tests in house.

What kind of reputation does the American Red Cross have for genotyping? How reliable are they?

I think that knowing your genotype is potentially useful information to have, especially as more becomes known. I do not think it can be used to diagnose the disease, but if you are symptomatic, respond positively to the diet and also have the genotypes typically associated with the disease then you have another piece of the puzzle to take to your doctor. It may be relevant or not as you say, but it gives a person more information. Plus it is kind of fun and I have certainly learned a lot.

I think you are absolutely correct about the testing giving people a sense of control. I think this is at the root of a lot of things you read on this board-- home gluten test kits, etc. Because we have this disease, so much of our lives is out of our control that I think we are desperate for anything that gives us a sense that we can control things, even a little bit. And if testing acomplishes this, then I think there is no harm in it.

The simple truth is that there are many things which medicine does not understand and most of us have fallen through the gaps in the system. What is truly unfortunate is when a doctor simply cannot bring himself (or hersalf) to say, "I just don't know."

Thank you for you post.

Lisa

[Jestgar]

Hi gfb1. I have a question for you.

Many of the people who get tested here do so through Enterolab. You will see many posts here regarding this company-- both positive and negative. If you read the fine print of the Enterolab genotyping results, they say they send their samples to the American Red Cross for typing. They do the other tests in house.

What kind of reputation does the American Red Cross have for genotyping? How reliable are they?

I know you addressed this to someone else, but I thought I'd answer anyway

Genotyping is incredibly easy. Incorrect results are usually a result of overinterpreting an assay that didn't work, and should have been repeated.

The Red Cross does HLA matching for transplants. Much bigger stakes than Celiac. I think they can be considered reliable.

Open Original Shared Link

[Lisa16]

Thanks Jestgar!

I had a feeling this was the case. :-)

[Mother of Jibril]

while some of my statements may seem bold, i'm not sure which are incorrect. genes of the major histocompatability locus are NOT celiac genes, per se. they may modulate immune response to particular antigens; one of which *may* be gluten-related (and this has NOT been proven) -- but, they do NOT cause the disease (there have been a handful of posts that address this point as well).

Very interesting! You're certainly a welcome addition to this forum

Actually, I didn't disagree with anything you said about genetics... and clearly you're the expert on this (my PhD is in a completely different field). My concern was that you were painting "celiacs" with an overly broad brush. Definitely there are lots of doctors and patients who are misinformed, BUT... I've met some people here who are really trying hard to get accurate information.

In any event... I still think it can be useful to know your HLA-DQ genotype. I went on a gluten-free diet after some questionable advice from an allergist. I think she assumed I would try the diet and go back to eating gluten... but I felt so much better! I knew I couldn't go back to a "normal" diet. When I found out that I have the DQ8 gene I felt like I really made the right decision With this information I was also able to convince my mom to get tested for celiac disease (with a blood test) and she turned out to be positive. I'm having my three-year-old daughter tested next.

[sbj]

tested individuals desperately need solid advice from a professionally trained geneticist -- not a medical doctor, nutritionist (and don't get me started on that -- see an RD for pete's sake), or representative of a testing laboratory. please consult a professional whose last genetics course (IF there was one) was taken more recently than their freshman biology class.

This is an interesting point and one with which I agree. In my own case, my Gastro ordered the genetic test only after a positive biopsy (via endoscopy) and positive celiac blood panel. He did this to help confirm his diagnosis. However, after the positive genetic test he did not request a referral to a genetics counselor. However, in a previous circumstance with the same health care provider, I had a positive genetic test for HNPCC (Lynch) but on that occasion I was referred to the genetics counselor.

So, at least in the case of Kaiser Permanente, it would appear that only certain positive genetic tests will result in a referral to a genetics counselor. I wonder why? Perhaps it has something to do with the perceived seriousness of the underlying condition?

[Jestgar]

I think that, in the case of HNPCC, there is a direct, verified, genetic link to the gene, whereas, the "Celiac genes" are neither necessary, nor sufficient, and therefor, not causal.

Knowing your HLA haplotype is interesting, but it doesn't really tell you anything about your reaction to gluten.

If you look Open Original Shared Link

and keep reading, you'll see that there are at least 13 sites that have been identified as increasing susceptibility to celiac disease.

[sbj]

I think that, in the case of HNPCC, there is a direct, verified, genetic link to the gene, whereas, the "Celiac genes" are neither necessary, nor sufficient, and therefor, not causal. Knowing your HLA haplotype is interesting, but it doesn't really tell you anything about your reaction to gluten. If you look Open Original Shared Link and keep reading, you'll see that there are at least 13 sites that have been identified as increasing susceptibility to celiac disease.

That makes perfect sense! It seems there is little value in the celiac genetic testing, but there is SOME value. (As I said, for confirmation and ...) For instance, if you are diagnosed with celiac via blood and biopsy and genetic capability, then it would seem that a gastro should refer you to a genetics cousnselor if only to explain to you that your children and/or siblings are considered increasingly susceptible to the disease? (I do understand, though, that markers don't indicate in any way that you are more likely to have the disease, only that you are capable. However, a diagnosis does indicate a greater likelihood that first-degree family members might have it.)

[gfb1]

wow. lots of interesting feedback!!

a couple of things offhand... i don't know anything about the red cross/blood testing (thanks jestgar!)-- although, i can tell you that i've often thought about what might happen if my wife received a transfusion with blood containing gliadin from an undiagnosed celiac.

not to be frightened over one more thing; but, the odds are probably a lot better than winning your state lottery.

i also don't know anything about enterolab. i do know that there are lots of places to get genotyped for nearly anything (as someone pointed out, it's getting easier all the time. phosphate chemistry has always been low-hanging fruit...... ). the trouble is, that -- aside from the feel-good part, which i will not offhandedly dismiss -- there is no context to interpret the data.

i also disagree with some details in a few prior posts. in no particular order;

gluten is not a toxin; our diets are not becoming loaded with grains -- if anything (esp in the us.of.a) our diets are loaded with meat; neither genes nor diet 'cause the disease' -- it is the interaction of the gene*diet that creates the disease situation. i have some thoughts on this... and will probably post a more cogent post at a later date. btw, all celiacs are not celiacs -- there are probably both genetic AND nongenetic types of gluten-sensitivity/allergy/etc.

genetic association and/or marker studies -- whether based on a known protein or a snp (single nucleotide polymorphism) -- are notoriously family-specific. that is, the marker may be predictive within the family in which it was identified, but of limited utility in the population at large. the statistical analyses themselves are exceedingly sensitive to mis-typed individuals. in the early days of marker analysis, there were nearly as many retractions as reports in the journal 'Science'. no doubt, the research has gotten better; but, as the article in my first post pointed out -- the work should not to be used for clinical diagnostics.

i find the associations to be academically interesting; but as a pragmatist, actually agree with one of the posts where there was the suggestion that 'if you are symptomatic, respond positively to the diet ' there is really no need to test anything. stay gluten free. the only reason to do anything else would be if the illness returns while on a gluten-free diet.

[gfb1]

That makes perfect sense! It seems there is little value in the celiac genetic testing, but there is SOME value. (As I said, for confirmation and ...) For instance, if you are diagnosed with celiac via blood and biopsy and genetic capability, then it would seem that a gastro should refer you to a genetics cousnselor if only to explain to you that your children and/or siblings are considered increasingly susceptible to the disease? (I do understand, though, that markers don't indicate in any way that you are more likely to have the disease, only that you are capable. However, a diagnosis does indicate a greater likelihood that first-degree family members might have it.)

agreed.

btw; the concept of inheritance pattern and concern for the risk for our children is HUGE. in our family pedigree; the inheritance pattern mimics simple recessive inheritance. however, i have read of other pedigrees that are not so clear-cut. further, it is important to point out (as my wife continues to remind me), that all non-celiacs may also be pre-celiacs due to variation in the age of expression.

[happygirl]

Welcome to the board, gfb1....I am enjoying reading your posts. Thank you for sharing your knowledge.

[lbd]

Hi again gfb,

I have to respectfully disagree with this portion of your reply:

"i also disagree with some details in a few prior posts. in no particular order;

gluten is not a toxin; our diets are not becoming loaded with grains -- if anything (esp in the us.of.a) our diets are loaded with meat; neither genes nor diet 'cause the disease' -- it is the interaction of the gene*diet that creates the disease situation."

Our diets are becoming extremely loaded with grains. Corn, soy, and wheat derivatives are used in nearly all processed food. While corn and soy do not contain gluten, certainly many wheat, rye, and barley derivatives do. Big agribusiness has convinced the government and people that we need whole grains to survive, when in fact, there are no nutrients in grains that cannot be found in other whole foods. IMO, very few humans have the genetic capacity to handle this influx of chemicals from grains, including the protein gluten. In my opinion, gluten is a toxin that many of us react to. Meat is not a problem - our ancestors had diets quite high in meats, fruits, and vegetables as whole foods. There is a problem with meat today, in that we feed livestock nearly exclusively grain diets that they, too, are not programmed to handle. Meat from grain fed beef is much higher in fat than grass-fed beef. Judging by what I observe my students eating, their diets are far more overloaded with sugar and grain-derived products than anything else. I suspect that some of them only get meat in a Big Mac. It is not quality stuff.

I also think I explicitly said genes do not cause the disorder, but can predispose one to developing the disorder if the environmental conditions are right (in this case, diet). On that point, we agree

Glad you are here- it's fun to discuss the science behind the effect gluten has on some.

Laurie

[Jestgar]

Hi again gfb,

I have to respectfully disagree with this portion of your reply:

An article addressing this:

Open Original Shared Link

Open Original Shared Link

[gfb1]

An article addressing this:

Open Original Shared Link

Open Original Shared Link

i always had a distaste for newspaper graphix (i spent too much time reading Open Original Shared Link )... Open Original Shared Link ... so; grain consumption is down significantly from the early 1900's ... but, up from 1970-ish. depending on how you count -- boneless/trimmed meat consumption in the US is at an alltime high of approx. 200 lbs./per person/per year.

[Jestgar]

Love Tufte! Thanks for the graphic. I found the other just as I was leaving work. Difficult to follow, but it did have the source noted on it.

[lbd]

Here's another article on wheat consumption which gives some historical reasons for the rise and fall of consumption over the last 100 years or so.

Open Original Shared Link

Most is tied to economic reasons and the slight decrease in the last decade is tied to the "low carb" phase that swept the country. Interestingly, the low carb fad in diets is what led me to link gluten with some of my own symptoms. Remove grains from diet = feel good, put grains back in diet = feel bad. No brainer. Meat consumption has risen because we feed cattle on the massive amounts of subsidized grain (mostly corn) we raise in this country thanks to the subsidies that Secretary Earl Butz put in place in the 70s that encourages agribusiness to raise more and more corn, wheat, and soybeans. Thus meat is relatively cheap and plentiful (and tasteless). I buy grass-fed beef from a local grower and they never see grain or antibiotics or steroids. Yum.

As a science geek, one thing I do know is that you can manipulate data in all sorts of ways to make your point.

How does all this link to genetics and gluten sensitivity? Beats me.

lbd

[Rebecca's mom]

Love all of the different opinions!

Then, there are those of us who have our family members tested because they won't start a gluten-free diet unless there are numbers "documenting" that they do, indeed, have a genetic predisposition and/or a higher than normal antibody level that isn't showing up on a blood test yet.

My dear hubby was exhibiting all of the symptoms of gluten sensitivity, but because his bloodwork didn't show definitive problems (only his gliadin antibody level was slightly elevated), he wasn't willing to go gluten-free. It was only after a lot of nagging on my part that he agreed to see what the genetic/stool tests showed. I agreed that if they didn't show a problem, I would quit nagging, so he had a vested stake in further testing!

Well, his numbers were indicative of a problem, so he has been gluten-free for 6 weeks now. He has grudgingly admitted that he has seen an improvement in the way that he feels; he came home today telling me that he must have gotten hold of something with gluten in it, because he had some significant GI issues after lunch, and he is still having discomfort.

The other good thing about testing with other companies is that we have "numbers" that we can show people who don't think that "this" is a real problem. Since having the testing done, our friends and family aren't giving us a hard time or rolling their eyes when we ask the staff about gluten-free options at restaurants - we try not to be obnoxious about it, but the way that we feel when we accidentally get hold of gluten isn't worth trying to "save face" in public.

Please continue to contribute to these forums - it is nice to have the wisdom of someone who is intimately involved with the genetics field who also has someone close with a celiac disease diagnosis!