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Celiac Disease Genetics

This article appeared in the Spring 2008 edition of Celiac.com's Scott-Free Newsletter.

Celiac.com 08/17/2008 - Are you confused about genetic testing for celiac disease? Do you want to know what tests you should request and which laboratory to use?  Have you already had celiac DQ genetic testing but are not sure what the results mean or what your risk is of developing celiac disease or gluten sensitivity? These are the questions I will answer in the next few pages. 

What is HLA DQ celiac genetic testing?
To understand celiac DQ genetics and the risk estimates you must also understand how the DQ types are determined and some basic terminology.  Each of us has 46 chromosomes, 23 pairs received from our parents.  We all have two copies of chromosome 6, one from each parent.  Homozygous is when a person has two copies of the same gene, one from each parent.  Our white blood cells (leukocytes) have proteins called human leukocyte antigens or HLA proteins that are inherited from our parents.  The genetic code that determines our HLA patterns resides on chromosome 6.  We all have two DQ patterns, one from each of parents, such that we are all DQx/DQx, where x is a number between 1 and 9.  I am DQ2/DQ7 and my wife is DQ2/DQ5.  We are both therefore heterozygous for DQ2.  That is, we have only one copy of DQ2.  Scott Adams, the founder of celiac.com is DQ8/DQ8.  He is homozygous for DQ8.  There are several HLA patterns.  Some are proteins that reside within cells and others are on the outer surface of cells, and are called class II.  The class II HLA proteins have very important immune functions.  There are several class II HLA protein types but DQ have been found to be important in celiac disease, specifically DQ2 and DQ8. 

What does it mean to be homozygous or heterozygous for celiac genes?
Homozygous means that you have two copies e.g.  DQ2/DQ2, DQ8/DQ8 whereas heterozygous means you have one copy of DQ2 or DQ8.  Some people have one copy of DQ2 and one of DQ8 (DQ2/DQ8) and they have a greater risk for celiac disease than someone with only one copy of either DQ2 or DQ8 but not as great a risk as someone with two copies of DQ2 (DQ2/DQ2).  Since DQ2 is associated with a greater risk of celiac disease than DQ8, then one copy of DQ2 plus a DQ8 (DQ2/DQ8) indicates a higher risk than having two copies of DQ8 (DQ8/DQ8).  Hopefully, I have not lost you yet but if I have please continue to read on because the information that follows will still be helpful to you.

What is this alpha and beta subunit typing and why is it important?
HLA DQ typing consists of two subunits of the DQ molecule, an alpha and beta subunit.  So, both DQ types that indicate a risk of celiac disease, DQ2 and DQ8, are made up of two protein subunits designated alpha and beta.  They determine the complex letter and number combinations reported.  For example, the full DQ2 molecule is typically HLA DQA1*05xx DQB1*02xx.  The A1 is the alpha unit and the B1 is the beta subunit. 

The beta subunit is the most important component of the DQ molecule, but the alpha subunit has also been shown to carry an increased risk for celiac disease.  Unfortunately, since testing for both is more complicated and expensive it is not always done. 

Also, some think that since the beta subunit carries most of the risk and the alpha unit only minor risk, testing for only the beta subunit is adequate.  Several clinical laboratories have chosen this approach.  They only test for, and report on, DQ2 and DQ8 based on beta subunit types, so their results typically look like this: HLA DQB1*02 detected, DQ2 positive, etc.  This is the policy of the laboratory at Bonfils, who also does testing for Quest Diagnostics and Enterolab as well as many hospitals.  However, the alpha subunit of DQ2 also carries some risk for celiac disease. 

What if you are positive for the beta subunit of DQ2 or DQ8 by testing from Bonfils, Enterolab or Quest?
If the beta subunit is present then Bonfils, Enterolab and Quest tests will report DQ2 and/or DQ8 positive.  Sometimes the report will just report DQ2 negative and DQ8 negative, especially when a hospital is reporting the results obtained from Bonfils.  However, when the beta subunit is not present and they report DQ2 negative and/or DQ8 negative, it is still possible that an alpha subunit could be present.  Results reported in this manner are, in my opinion, potentially misleading.  I believe they can lead a doctor to assume that an individual is not at increased risk for, or cannot have celiac disease, when this may or may not be true.  Unfortunately, the patient in such circumstances may be told that they can not have celiac disease, yet they may not only be at risk for the disease, they may well have it while being told it is impossible or extremely improbable. 

What does Prometheus do and how do they report their results?
Prometheus, like Kimball and LabCorp, includes alpha and beta subunit typing.  In the past they did not indicate whether there was one or two copies of DQ2 or DQ8 if someone was positive.  If a patient was DQ2 and DQ8 positive then these labs reported their full genetic DQ type.  However, if one or the other was negative, their exact genotype was not reported.  Recently, not only has Prometheus started reporting the full DQ2 and DQ8 genotype, but they are now reporting whether someone is homozygous or heterozygous as well.  They are also reporting the relative risk for celiac disease based on the pattern shown by testing.  However, they are still not reporting the other DQ types. 

What is the advantage of the new Prometheus reporting?
Since Prometheus results now include a calculation of the individual’s risk of celiac disease, compared with the general population, the patient can see how high their risk of celiac disease is, as well as being able to estimate the risk for their parents and their children. 

As you can see, the risk of celiac disease has a wide range of possibilities, which depend on the individual’s DQ results.  This risk can be below 0.1% if you do not have any portion of the high-risk genes DQ2 and DQ8.  On the other hand, the risk may be very high (more than 31 times the risk of the general population) if you have two copies of the full complement of DQ2 molecule.  Again, I would like to point out that if you have DQ2/DQ2, DQ2/DQ8, or DQ8/DQ8, then both of your parents and all of your children have to have at least one copy of an at-risk celiac gene.  Your child’s complete type will depend on the DQ contribution from their other parent. 

What other laboratories do both alpha and beta subunit testing?
Kimball Genetics and LabCorp also report both alpha and beta subunit results but the advantage of their testing is that they report the other specific DQ types detected.  Gluten sensitivity is found in all DQ types except DQ4.  Other DQ types, particularly DQ1, DQ5, are associated with a risk of gluten related neurological and skin problems.  Microscopic colitis, food allergies and oral allergy syndrome reactions are also found in association with other DQ types.  Though Enterolab does report other DQ types, including these markers of risk for gluten sensitivity, they do not test for, or report, alpha subunits since their DQ testing is done by Bonfils.  Based on the limited data I have accumulated so far, DQ2 and DQ8 also seem to carry a risk of mastocytic enterocolitis. 

What if you do not have DQ2 or DQ8?
According to data accumulated, but as of February 2008, not yet published by Dr. Ken Fine, unless you are DQ4/DQ4 you are still at risk for being sensitive to or intolerant of gluten.  According to Fine’s fecal gliadin antibody data all DQ types except for DQ4 carry a risk of gluten sensitivity.  My clinical experience supports this claim.  The presence of one copy of DQ1, DQ3, DQ5, DQ6, DQ7, or DQ9, even with one DQ4, is associated with a risk for elevated stool gliadin antibody and symptoms of gluten sensitivity that responds to a gluten free diet. 

What if your genetic testing was done by Enterolab, Quest, Bonfils or a hospital that utilized Bonfils, and it indicated that you were DQ2 and DQ8 negative? 
Since Bonfils does not test for the alpha subunit and they perform the testing for Enerolab and Quest, you may not be completely negative for DQ2 or DQ8.  You do not have the beta subunits associated with the highest risk for celiac disease.  For example, you could be “half-DQ2” positive and still be genetically at risk for the autoimmune form of gluten sensitivity that we know as celiac disease, along with all of its risks. 

What if you have not yet had celiac DQ genetic testing? 
I recommend that everyone have the testing.  I realize that most insurance companies and doctors, including some celiac experts, would disagree with me.  However, the value of DQ testing is that it can provide a great deal of information about your risk, especially if you have testing done for both alpha and beta subunits.  I recommend that you have testing done by Kimball Genetics, LabCorp or Prometheus if you have not yet had genetic testing done.  If your insurance or budget does not allow for this more expensive testing, but does cover testing by Quest or Bonfils or you can afford the $159 that Enterolab charges, then I still recommend that you get DQ testing using one of these laboratories.  You just need to be aware of the limitations of the results as I have reviewed them here.

What are the advantages of DQ testing through Kimball Genetics?
Kimball can perform testing on either blood or mouth swab samples.  The tests can be ordered without a doctor’s order.  You can purchase testing on mouth swab sample for $345.  The advantages of Kimball’s tests include alpha and beta subunit testing and full DQ typing to determine if you carry the other gluten sensitive DQ patterns besides DQ2 and DQ8.

What about LabCorp?
LabCorp also provides both alpha and beta subunit testing and they report the other DQ types.  They only provide testing on blood samples, a doctor must order the testing, and preauthorization is required. 

Do health insurance companies cover celiac DQ genetic testing?
Many but not all health insurance companies cover HLA DQ testing and almost all require preauthorization.  The ICD9 diagnostic codes that typically are honored are V18.5 genetic predisposition for gastrointestinal disease; V84.8, genetic predisposition for other diseases; and 579.0, celiac disease. 

Why are the genetics so difficult to understand and why are so many doctors either unaware of the testing or reluctant to order the tests?
I write and speak about DQ genetic testing frequently, and try to get testing for as many of my patients as possible.  However, many insurance companies will not cover the cost of these tests.  Most primary care doctors and even some GI doctors are completely unaware of the existence of a genetic test for celiac disease.  The testing is difficult to understand and the reporting by some labs is very confusing and even misleading. 

I realize that understanding the DQ genetics is difficult for the average layperson.  Most scientists and doctors don’t understand this information, so don’t despair if you are having difficulty following this or understanding your results, and don’t be surprised if your doctor does not understand them either.  However, you do not need to completely understand the complexities of HLA typing to locate your DQ types and determine your risk of celiac disease, non-celiac gluten sensitivity, etc. 

Then what do you need to know or remember about celiac DQ genetics?
Hopefully, you now understand enough to know that you should consider having celiac DQ testing, if possible, especially if you have symptoms, laboratory tests, or an intestinal biopsy that is suggestive of celiac disease.  You should also know that the testing can be done on blood or mouth swabs, and many insurance companies will cover the testing but most require pre-authorization.  You should also be aware that the testing is available without a doctor’s order, if you are willing to pay for it, and that some tests are better than others.  I also hope you understand that the tests can help you determine your risk for celiac disease or if you are at risk for non-celiac gluten sensitivity.  You should also know that your results, especially when combined with those of one or more family members, may help you determine, to some degree, the risks for your parents and your children.  You should also know what laboratories offer testing, what test codes your doctor should use to order the tests, and that the absence of DQ2 or DQ8 does not exclude risk of gluten sensitivity or intolerance.  Depending on what laboratory conducts your DQ testing, your results also may fail to exclude your risk of celiac disease. 

What if I am still confused or I don’t know how to interpret my genetic results or my previous evaluation for celiac disease?
If you are still confused by your test results or want more a personalized review of your results, symptoms or diagnostic tests I recommend that you see a physician who is an expert in celiac disease and understands these tests.  I also offer on-line consultation for a reasonable fee through a secure consultation site, www.medem.com.  You simply register (registration is free) for secure on-line communication and request a consultation.  The consultation fee is $50, and some insurance companies will cover on-line communication.  I also see many patients from outside of Colorado Springs for consultation if you are willing to travel here. 

Celiac.com welcomes your comments below (registration is NOT required).



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37 Responses:

 
Frances Collier, MT, VMD
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said this on
26 Aug 2008 9:45:47 AM PST
Excellent information. But we are still assuming that certain genes like to travel together and therefore certain white cell antigens travel with the genetic determinants of celiac disease. Will there eventually be a specific chromosome test for celiac?

 
Katherine Robertson
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said this on
26 Aug 2008 1:29:57 PM PST
Great information!

 
Sandy M
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said this on
30 Aug 2008 8:46:05 AM PST
Great article

 
Diane Dreiling
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said this on
31 Aug 2008 3:36:26 PM PST
I understood the explanation! I will send this to my [grown] son to present to his family physician who seems to resist allowing my son to be tested.

 
Susie
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said this on
01 Sep 2008 6:39:01 PM PST
One of the most informative and understandable articles I've read in a very long time. Thank you!

 
Blondy
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said this on
02 Sep 2008 11:24:29 AM PST
Very explanatory article. Thank you!

 
Janet
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said this on
02 Sep 2008 6:57:06 PM PST
This is the best explanation that I have seen thus far that is in understandable layman's terms. I'll pass it on to my daughter who often wonders if she, too, will become a celiac

 
debslo
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said this on
03 Sep 2008 3:33:38 PM PST
Thank you for this article! I was just attempting to figure this out by discussing this with a fellow boardie this past month. While your 'Ten Facts' article was great, this article makes things as crystal clear as it can for the lay-person, and now I have better understanding for what our fellow boardie was sharing and then some!

 
Beatrice
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said this on
18 Sep 2008 8:30:52 AM PST
Genetic testing should be a part of every family's medical regimen. Speak to your congressional representative. The later a person is diagnosed with celiac disease or any other inherited disorder the more damages a person must attempt to overcome. Seems to me an obvious course of action.

 
Tammy
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said this on
01 Nov 2008 7:09:52 PM PST
Excellent Article... it has been very helpful and we appreciate your clear communication. Our family bears out the research on genetic testing and specific alpha and beta sub-unit findings you mention here.

 
G. F. Barbato
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said this on
03 Feb 2009 6:53:41 AM PST
I have been a 'working' geneticist dealing with a variety of species for the past 30 years. My wife and her family have been identified as having celiac disease -- hers being one of the horror stories of being caught in the 'system'.
However, I find the emphasis on HLA typing to be misguided. HLA types 'may' be associate with risk factors -- but, these are fundamentally no more than simple correlation analyses and say nothing of causation. therefore, I would truly recommend against calling them 'celiac genes'. More than likely, the HLA subtypes determine the immune response of the individual when exposed to the gluten/gliadin (or possibly other) amino acid sequences. The true 'gene' for celiac -- if there is such a thing -- is more than likely an enzyme that prevents complete digestion of the glutamine-rich portion of the gluten molecule. Of course, this means that one should understand celiac disease as a 2-stage disease. The first being exposure to the antigen and the second being responses to that antigen. I strongly suspect that the DQx series of HLA subtypes are involved with the latter and NOT the former.

 
Jeff Kelly
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said this on
05 Jun 2014 7:09:40 AM PST
You have not read the studies of Allessio Fasano MD et al out of University of Maryland. Celiac disease is more than merely a two stage disease. At the genetic level it may be, but there is a prior level of pathyphysiology which also applies, meaning, the abnormal increase in zonulin hormone, which starts the process of "leaky gut", leading to the other stages of the disease process. What is not yet elucidated is the nexus between ingestion of glutens by the celiac and starting the process of zonulin increase to abnormal ranges, which appears to be the biologic missing link to the entirety of the pathophysiologic process.

 
G. F. Barbato
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said this on
03 Feb 2009 8:47:59 AM PST
One more thing. IMHO, genetic testing should NOT be part of 'every family's medical regimen'. Most people and a majority of doctors don't know a thing about simple mendelian inheritance -- not to mention complex multifactorial diseases. To arbitrarily test for something with no knowledge of meaning or context is just plain irresponsible. I recognize that there are a lot of people in pain and misery -- desperate for a solution, heck, even a piece of the question. But, snake-oil don't cut it.

 
Marie
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said this on
21 Apr 2009 2:01:34 PM PST
It is not possible to get this genetic testing in my large city in Canada. My daughter had been suffering with diarrhea, nausea, bloating, pain, pale for several years. Also as a student relying on pasta, pizza etc.
I have an autoimmune disease (Sjogrens) & a bad rash so I went to Scripps in La Jolla,Ca. They didn't help my rash but blood tests came back HLADQ2, & they said get more tests but they won't do them here. We sent daughter to our Dr. & a blood test suggested Coeliac but she would need to wait 6mths for biopsy & eat gluten! We paid to fly her to another province where she found out the same day for $500, plus hotel & airfare. Villi were flat,she has a picture. So much for our medicare system! Be careful what you wish for.

 
Kirsti
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said this on
27 Oct 2009 9:24:22 PM PST
Marie,
Trust me, our medicare is so much better! We live in Montreal but since my daughter had her US university insurance, I allowed her to have her biopsy there (also, it went faster there than here). Our portion of the cost of the biopsy was $10,000! The US system sucks. Also, my son with his Harvard health insurance had to pay $14,400 for room and board (!) for one night stay at a hospital. Only medical procedures were covered not room and board. Your $500 plus hotel was nothing compared the madness that is the US. I'm so grateful to live in Canada.

 
Renee
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said this on
05 Oct 2011 3:19:39 PM PST
Marie,

I second Kristi, what you described was inconvenient, but not devastating! I am a student with private insurance because the school insurance is a waste of money. Even still, the insurance I have is not very good. My deductible is $2,500 and I pay $350 a month for insurance. After I meet my deductible my insurance will only cover 75% of some not ALL procedures (and they get to decide what those are - they didn't even want to pay to sedate me for an endoscopy & colonoscopy which were done on the same day in succession of each other). If not for my parents stepping up to pay the deductible I would never have been able to even get the diagnostic tests done. To add insult to injury the surgery center & labs charge me the same inflated rate they charge the insurance company who has deeper pockets than I do, which means instead of paying $164 for a procedure I pay $1,000. Still want to trade health care systems?

 
Halllie
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said this on
29 Apr 2009 12:49:31 PM PST
G. F. Barbado wrote: 'The true 'gene' for celiac -- if there is such a thing -- is more than likely an enzyme...'

Sorry, but this is false. Genes are DNA, not protein. They CREATE proteins. The HLA proteins are each created by a certain gene. Certain of these HLA proteins have been shown to be associated with an increased risk of celiac disease, so it may be safe to say that the corresponding genes which created them are associated with this increased risk. That it is why it is easiest to say 'The HLA DQ8 gene,' rather than saying 'the gene that codes for the HLA DQ8 protein.'

Now certain proteins also have an enzymatic function. Enzymes are proteins which serve as catalysts (speed up) certain biochemical reactions. It's quite possible that these HLA proteins either do mediate biochemical reactions in some altered fashion, or have defective ability to catalyze certain reactions?!

This was an excellent article!

 
david turkheimer
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said this on
20 May 2009 6:58:26 AM PST
I wish I had your article in hand when I reviewed the test I had a few years ago. The doctor (and this was at the Columbia University Celiac Center) said that she couldn't confirm celiac from the genetic result (and I was already symptomatic!).

 
Crayons574
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said this on
31 May 2009 12:24:55 PM PST
This is an excellent article! So well written--understandable and with thorough explanations. Thank you!!

 
Joan White
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said this on
20 Jul 2009 6:13:23 PM PST
What a great, simple to read, informative article. Many thanks for the clear explanation. As someone with HLA2,2 and symptoms, this article helps me understand celiac disease and GSE even if my gastroenterologist doesn't.

 
Kris
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said this on
20 Oct 2009 10:43:26 AM PST
Halllie, your response, "Now certain proteins also have an enzymatic function. Enzymes are proteins which serve as catalysts (speed up) certain biochemical reactions. It's quite possible that these HLA proteins either do mediate biochemical reactions in some altered fashion, or have defective ability to catalyze certain reactions?!" strikes a nerve with me. I have had RA for most of my life (JRA to be precise) and my gluten issues started around the same time I started Enbrel, an RA med, which is an injectible protein. I have no scientific knowledge to back up my hunch but I often wondered if the Enbrel, which does an amazing job on my RA, was the catalyst that caused the gluten issues to surface. I'm awaiting test results to see if I have celiac. I'm pretty sure I do since my symptoms go away with a gluten-free diet. I'll be sure to re-read this article once I get my results so I can understand what's going on. BTW, my rheumatologist knew nothing about celiac. From everything I've been reading it seems as if any doc who has patients with a auto immune disease need to be reeducated about celiac. I'm in a high risk group and I wish that when I started complaining about these GI issues 6 years ago a doc would have put 2 and 2 together. Alas, like so many of you, I've been left to figure this out on my own. I live in a big city and go to an award winning hospital for care so there's no excuse. I guess you can say I'm in the anger phase of the gluten free journey.

 
JON
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said this on
22 Dec 2009 12:00:01 AM PST
This article should be distibuted to every GP in the UK

 
Betty Beyea
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said this on
20 Jan 2010 6:46:24 PM PST
Thank you!
Five years ago I found the only test I could trust was the blood test for the gluten gene. Celiac is certainly in my families.

 
Cheryl
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said this on
22 Feb 2010 1:27:44 PM PST
This article was very helpful and informative.

 
Ray
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said this on
24 Feb 2010 1:35:35 AM PST
Excellent article. Thank you for clarifying so much of this subject. I am interested in the parallels and correlations in genetic testing for diabetes. The doubled risk for diabetics of celiac disease poses the question, what genetic pointers do the two diseases have in common?

 
coco
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said this on
23 Mar 2010 8:32:27 AM PST
good job

 
keri Brooks
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said this on
17 Apr 2010 9:58:13 AM PST
I recently had a client go through Kimball Genetic instead of Enterolab, based on this article where Dr. Lewey states that Kimball tests for all celiac alleles as well as other alleles associated with gluten sensitivity but this doesn't appear to be the case?!?!?!? Enterolabs identifies which alleles you actually have verses Kimball Genetics which only identifies if you test positive for the specific celiac alleles but non associated with gluten intolerance. In my experience having one or two gluten sensitivity genes can be just as severe as being diagnosed as a celiac in which case knowing if you have a predisposition to gluten sensitivity is important too.

 
Gillian Ping
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said this on
24 Jun 2010 12:52:45 AM PST
Really brilliant. I would suggest every person underwent this testing as I have lived with celiac for 35 years and only discovered it 5 years ago after almost dying before anyone did anything. Thanks again.

 
Judy Baldwin
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said this on
09 Jul 2010 12:56:13 PM PST
Thank you, thank you, thank you! I now understand the results of my genetic testing much better. You opened a window of knowledge for me.

 
Susan
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said this on
14 Jul 2010 1:27:16 PM PST
Fantastic! I am of Northern Italian lineage. In Italy one day a month is allowed a free day by the government to take the day off to buy non-gluten ingredients because gluten intolerance is highly prevalent throughout Italy. I have been gluten-free for about 4 years now. After years of horrible symptoms. Tapioca watch out for side effects and soy as they may upset the thyroid. Also Mexican Coca-Cola was told to me this morning by the 800 rep line to be gluten-free. This website is a lifesaver. Susan :-)

 
Tim
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said this on
15 Aug 2010 10:15:43 AM PST
I greatly appreciate the specifics on the best lab tests and their availability! I can see that gene testing might be of some benefit for individuals but I see a greater benefit for society as a whole if the test results were anonymously gathered in a database along with some demographics. I hope that the creator/s of celiac.com give this recommendation heavy consideration. Can't you just imagine how quickly such data would aggregate in a social media network like this one? And you wouldn't even have to pay a research company for the data!

 
Patty
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said this on
09 Jan 2011 11:50:35 PM PST
hmm...the information about gluten free foods not containing enough vitamin b, iron and zinc is very contradictory to the link given...all the foods listed in the link have no gluten! I'm just learning about gluten-free and because my dad and cousin both have celiac and break out in crazy allergic reactions when they have gluten and msg...trying to protect myself early.

 
Joan Gans
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said this on
14 Sep 2012 12:30:38 PM PST
my test showed DQ2 Homozygous 31X
DQ2/other high risk gene 16X
DQ2/DQ814X
DQ8 Homozygous 10X
DQ2Heterozgous 10X

 
Tammie
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said this on
04 Nov 2012 6:43:56 AM PST
My husband has been diagnosed with celiac after a very long battle. I think that this testing should be done on everyone to help prevent our downward spiral of disease. Not to mention the savings for our healthcare system, if we knew we are predisposed to celiac disease. My feeling through my own research is that no one should consume gluten in any form! People take charge of your health because most MD's just don't have a clue about this problem. Spread the word, and possibly help someone else who is struggling.

 
Jenna
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said this on
25 Jan 2013 9:39:38 AM PST
This was an amazing article and it really helped me.

 
Janice Marela
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said this on
22 Jun 2013 5:39:46 AM PST
Excellent article. Just wondering if someone has had the celiac gene. I had testing done and I was shown to have a high genetic risk for developing celiac disease (1:35). What would the next steps be? Past celiac blood tests have been negative and the same with the intestinal biopsy.

 
Maura
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said this on
18 Jun 2014 3:52:44 PM PST
This is the best explanation of HLA testing for celiac disease I have ever seen. Thank you so much!




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