Understanding the Genetics of Gluten Sensitivity

By Dr. Scot Lewey

All of us have patterns of proteins on the surface of our white blood cells. The proteins are known as human leukocyte antigens (HLA), one of which is DQ. Celiac Disease (CD) and non-Celiac gluten sensitivity (NCGS), and several autoimmune conditions occur more frequently with certain HLA DQ types. DQ gene testing is performed by analyzing cells from a blood sample or from a Q-tip swab of the mouth. HLA types have a naming system that can be confusing even to scientist and physicians but here is my explanation of the testing, the results, and what they may mean to you and your family.

Each of us has two copies of HLA DQ. Because there are 9 serotypes of DQ we are all DQx/DQx where x is a number between 1 & 9. For example, I am DQ2/DQ7. I received the DQ2 from one of my parents and the DQ7 from the other. Because we get one DQ type from each of our parents and give one to each of our children it is easy to to see how the DQ genes pass through a family. This is important because two DQ types, DQ2 and DQ8, are estimated to be present in over 98% of all people who have Celiac disease, the most severe form of gluten sensitivity.

Rarely, true Celiac disease or dermatitis herpetiformis, the skin disease equivalent of Celiac, have been reported to occur in people who do not have DQ2 and/or DQ8. However, according to unpublished data from Dr. Ken Fine of Enterolab, the other six types, except DQ4, are associated with risk of elevated stool antibodies to gliadin, the toxic fraction of gluten, and/or tissue transglutaminase (tTG) an enzyme. Both of these antibodies are usually elevated in the blood of individuals with Celiac disease though they may be normal in the blood of individuals who are gluten sensitive and have a normal small intestine biopsy but respond favorably to a gluten-free diet.

Fine has publicly reported that elevated stool antibodies to gliadin and/or tTG have been detected in all of the untreated Celiacs tested in his lab, 60% of non-Celiacs who have symptoms consistent with gluten sensitivity, but in none of the controls tested including cow manure. Follow up surveys of those individuals with elevated stool antibodies who initiated a gluten-free diet compared with those with elevated antibodies who did not reportedly showed significantly improved quality of life and symptoms in the gluten-free group.

He also reported DQ2 and DQ8 positive individuals, have had as a rule the highest elevations of stool gliadin antibody followed by those who are DQ7 positive. Only those who are doubly positive for DQ4 have not been found to have significantly elevated antibodies to indicate gluten sensitivity. This is consistent with the differences in prevalence rates of Celiac disease seen in parts of the world. Since DQ4 is not generally found in those of Caucasian race of Northern European ancestry, where Celiac incidence is highest, but in those from Asia or Southern Africa where there is a very low incidence of Celiac disease and gluten intolerance.

DQ2 & DQ8, the two major types, are present in 90-99% of people who have Celiac disease. They are also present in approximately 35-45% of people in the U.S., especially those of Caucasian race of Northern European ancestry. The prevalence in the U.S. of Celiac disease is 1% and though a prevalence of 1 in 100 is very common and much higher than had been believed for years, this is only a fraction of the genetically at risk that actually are confirmed to have Celiac disease by abnormal blood tests and small intestine biopsies. However, the number of people who report a response to a gluten-free diet is much higher.


Stool antibody test results would support this and the concept of a spectrum of gluten sensitivity that is much broader and in need of better diagnostic definitions. I am an example of someone who is DQ2/DQ7 who has normal blood tests for Celiac disease but abnormal stool antibody tests and symptoms that have responded to a gluten-free diet. The strict criteria for diagnosis of Celiac disease by abnormal blood tests and a characteristic small intestine biopsy showing classic damage from gluten is much narrower than what is being seen clinically.

It is becoming obvious to many of us who have personal and professional medical experience with gluten intolerance and Celiac disease that the problem of gluten sensitivity is much greater and extends beyond the high risk Celiac genes DQ2 and DQ8. Traditionally it is reported and believed by many that if you are DQ2 and DQ8 negative you are unlikely to have Celiac disease or ever develop it. This cannot be said with 100% certainty especially since there are documented cases of Celiac disease and the skin equivalent of CD, known as dermatitis herpetiformis (DH), in individuals who are DQ2 and DQ8 negative.

Knowing your DQ specific serotype pattern may be helpful for several reasons. If you have more than one copy of DQ2 or DQ8 you carry two of the major genes. For example if you are DQ2/DQ2, DQ2/DQ8, or DQ8/DQ8, a term Scott Adams of http://www.celiac.com has dubbed a “super celiac”, you may be at much higher risk for Celiac disease and have more severe gluten sensitivity. Certainly if you are DQ2 and/or DQ8 positive you are at increased risk for Celiac disease. After a single copy of DQ2 or DQ8, it appears DQ7/DQ7 might be next highest risk. Dr. Fine has also noted some other associations with the DQ patterns with microscopic or collagenous colitis, neurologic manifestations of gluten sensitivity and dermatitis herpetiformis, which has been one of the gluten sensitive conditions noted to be at times occurring in DQ2, DQ8 negative individuals.

Why some people get Celiac Disease or become gluten sensitive is not well understood. Certain factors are believed to trigger it including the onset of puberty, pregnancy, stress, trauma or injury, surgery, viral or bacterial infections including those of the gut, medication induced gut injury or toxicity e.g. non-steroidal anti-inflammatory medications such as aspirin, ibuprofen, etc., immune suppression or autoimmune diseases. There is also a well known group of individuals who are termed “latent” Celiacs. They are those at high risk because they have close relatives who have Celiac disease with whom they share one or more of the Celiac genes DQ2 and/or DQ8. Though they usually have little or no symptoms they may have abnormal blood tests and/or biopsies indicating possible or definite Celiac disease. Others have negative blood tests and normal biopsies but symptoms that respond to a gluten-free diet.

The severity of the sensitivity to gluten does appear to be related to the DQ type, family history (highest risk is in the non affected identical twin of a Celiac), pre-existing intestinal injury, degree of exposure to gluten (how frequent and large a gluten load an individual is exposed to), and immune status. Once initiated, gluten sensitivity tends to be life long. True Celiac disease does require lifelong complete gluten avoidance to reduce the increased risk of serious complications such as severe malabsorption, cancers (especially of the GI tract) lymphoma, other autoimmune diseases and premature death due to these complications.

Again, DQ testing can be done from cells from blood or by a swab of the inside of the mouth but not all labs test for or report the full DQ typing but only the presence or absence of DQ2 and DQ8. The lab that performs DQ testing is usually determined by an individual insurance company on the basis of contracts with specific commercial labs. However, if your insurance contracts with Quest Labs or the Laboratory at Bonfils (Denver, CO) full DQ can be done if ordered and authorized by the insurance company.

For those willing to pay out of pocket, Bonfils performs full DQ testing for Enterolab (www.enterolab.com) on a sample obtained by a Q tip swab of the mouth. Since it is painless and non-invasive it is well tolerated especially by young children. Also because the testing can be ordered without a physician and the sample obtained in their home using a kit obtained from Enterolab it is convenient. The kit is returned by overnight delivery to Enterolab who forwards the test onto Bonfils. The cost is $149 for the genetic testing alone and has to be paid for in advance by credit card or money order and is generally not reimbursed by insurance.

Enterolab also provides the stool testing for gliadin and tissue transglutaminase antibodies to determine if gluten sensitivity is evident. The gliadin antibody alone is $99 or the full genetic typing, stool testing for gluten and cow’s milk protein antibodies, and a test for evidence of malabsorption is $349.

Again, the advantages of full DQ testing is to determine if someone has one or more copy of DQ2 or DQ8 or carry both and therefore have a higher risk for Celiac disease or more severe gluten intolerance. If you are DQ2 or DQ8 negative then your risk of Celiac disease is low, though not non-existent. If you are not DQ4/DQ4 then you do have a risk for gluten sensitivity. If you determine the full types within enough family members you can piece together a very accurate history of the origins of Celiac and gluten sensitivity within a family and make some very accurate predictions of risks to other family members.

Though the lay public and many clinicians are finding the genetic tests helpful, many, including most physicians, do not understand the genetics of gluten sensitivity. We are awaiting Dr. Fine’s published data on the significance of stool antibody tests and their association to the other DQ types as his lab is the only lab offering the stool antibody tests in the U.S. Other Celiac researchers in U.S. have failed to reproduce his assay but scattered reports in the literature are appearing including a recent article in the British Medical Journal indicating stool antibody testing is feasible, non-invasive, and using their protocol, highly specific but not sensitive for Celiac disease in children.

In the meantime, many patients are faced with whether the failure of traditional blood tests, small bowel biopsies, and the presence or absence of DQ2 and DQ8 to diagnose or exclude gluten sensitivity justifies the uncertainty and added cost of full DQ testing and stool testing. Physicians unfamiliar with this testing are increasingly being presented with the results and confused or skeptical pending published results. There also continues to be a lack of consensus in the medical community regarding the definitions of non-Celiac gluten sensitivity and what tests justify recommendations for gluten-free diet. It is clear though that gluten sensitivity by any criteria is much more common than ever thought and a hidden epidemic exists.

Scot M. Lewey, D.O., FACP, FAAP
�The Food Doc�

Dr. Scot Lewey is a physician who is specialty trained and board certified in the field of gastroenterology (diseases of the digestive system) who practices his specialty in Colorado. He is the physician advisor to the local Celiac Sprue support group and is a published author and researcher who is developing a web based educational program for people suffering from food intolerances, http://www.thefooddoc.com

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