Update on genetics of celiac disease

Genetic tests exist for Celiac disease and are highly accurate for determining the risk of the disease. When a complete genetic panel is performed the possibility that someone having or ever getting Celiac disease can be determined to an extremely high degree of certainty. Unfortunately, some tests are misleading because they do not include a portion of the genetic pattern that may be present that can predispose to the disease yet the report may imply absence of increased risk.

Some tests can be done without a doctor’s order. Insurance coverage for the tests is highly variable. A couple of laboratories can run the tests on samples obtained from a mouth swab that is painless and well accepted by children. Genetic testing can be done at any age whereas blood tests for Celiac disease are not recommended before a year of age. Celiac disease genetic tests are not influenced by whether one is eating or not eating gluten.

If you do not have the commonly recognized genetic patterns associated with Celiac disease you are generally excluded from the risk of ever getting the full autoimmune disease and don’t need to be periodically retested though you can be intolerant or sensitive to gluten. This can be very helpful for those who have a family member with Celiac disease or other autoimmune diseases associated with at risk Celiac disease genetics.

HLA DQ2 and DQ8 are the simplified white blood cell patterns or types that are known to be associated with an increase risk of Celiac disease and one the necessary requirements to develop the disease. The HLA term stands for human leukocyte antigen. Leukocytes are white blood cells. Antigens are proteins that serve or elicit an immune response by the body. So, the HLA system is a complex set of proteins on the surface of white blood cells.

These protein patterns are inherited just like the red blood cell proteins that constitute what is commonly known your “blood type”. I, for example, am A positive blood type. This means I have a pattern of proteins designated A and Rh+ on the surface of my red blood cells. On the other hand I have a white blood cell type pattern DQ2/DQ7 inherited from my parents. My Dad gave me a DQ2 and my Mom the DQ7. You have two DQ patterns on your white blood cells that you received from your parents and you give one of your DQ types to each of your children.

Since only a single copy of either DQ2 or DQ8 can be associated with an increase risk of developing Celiac disease, most laboratories test for the presence of either and simply report their presence or absence. However, knowing if you have one or two copies not only provides additional information about degree of your risk and possible severity of Celiac disease but also information about your parents and your children’s risk of inheriting an at risk gene. If you have DQ2 and DQ8 we know your complete DQ pattern as well that both your parents and all of your children have or will get at least one at risk gene.

Other non-HLA genetic factors are involved in the risk of Celiac disease. These are still being worked out. However, one poorly understood and little known fact to most doctors and almost all patients is that HLA DQ2 and DQ8 testing done by some laboratories does not include the full spectrum of at risk components of these patterns. DQ2 and DQ8 are a summary blood type designations or serotypes for the presence of several protein subunits. There are alpha and beta subunits to these protein patterns. The beta subunit is the most influential and important component. Most laboratories only test for and report the beta subunit. However, the alpha subunit does carry risk on its own, albeit much less than the presence of the beta subunit or the presence of both alpha and beta subunit.

The most commonly used laboratories for Celiac disease genetic testing in the U.S. are Kimball Genetics, LabCorp, Quest, Prometheus, and Enterolab. The Laboratory at Bonfils in Denver not only provides testing directly but also does the testing for several hospitals, Quest and Enterolab. Bonfils only does beta subunit testing. They report results of DQ2 and DQ8 negative based on the absence of the beta subunits associated with DQ2 and DQ8 however this is misleading since someone could have only the alpha subunit and be “partially” DQ2 or DQ8 positive.

Though the risk of being “half” DQ2 positive from only having the alpha subunit is low overall it is still there. Furthermore, there are people who may believe that they are DQ2 or DQ8 negative based on testing from Bonfils, Quest or Enterolab, therefore they and/or their doctor may exclude the possibility that they have or are at risk for ever getting Celiac disease when in fact this may not be true.

The existence of DQ2 and DQ8 negative Celiac disease has been debated and is clouded to some degree by this confusion. Most Celiac experts assert that the presence of DQ2 or DQ8 is a requirement to develop the disease and their absence excludes the possibility. However, reports of DQ2 and DQ8 negative Celiac disease persist.

I have a couple of patients who have the specific blood tests for CD, endomysial and tissue transglutaminase antibody, and the classic biopsy features that were reported DQ2 and DQ8 negative by laboratories who only test for the beta subunit. Re-testing for alpha unit positive “half” DQ2 or DQ8 is being requested on these patients. However, I am deeply concerned that many patients and doctors may have been lulled into a false sense of security or diagnoses of Celiac disease may have been withdrawn on some individuals based on incomplete genetic results.

The issue of DQ2 and DQ8 testing is further complicated by reviews on the subject that are incomplete or vague. The best reviews I have found are by Ludvig Sollid and Benedicte Lie of Oslo, Norway “Celiac Genetics: Current Concepts and Practical Applications” Clinical Gastroenterology and Hepatology 2005 and Bourgey’s 2007 review. In a recent update article by Victorien, there is a general review the genetics of celiac disease including the association of myosin IXB gene (MYO9B). However, it doesn’t explain the DQ2 or DQ8 typing well. They conclude that “To date, only HLA-DQ2 or HLA-DQ8 typing is clinically relevant…” but fail to point out that HLA DQ2 and DQ8 typing should include both alpha and beta subunits.

It is clear that both HLA and non-HLA genetic factors are important in the risk of celiac disease. However, the absence of the celiac disease high-risk genes does not preclude adverse reactions to gluten including leaky gut, skin, digestive and neurological symptoms. When genetic testing is used to try to assess the risk or exclude celiac disease then I recommend that full testing including both alpha and beta subunit typing. Hopefully more research will better define the genetics of both celiac disease as well as non-celiac gluten sensitivity or gluten syndrome.


Selected References:

Bourgey, M et al. HLA related genetic risk for coeliac disease. Gut 2007; 56:1054-1059.

Johnson, TC et al. Relationship of HLA-DQ8 and severity of celiac disease: Comparison of New York and Parisian cohorts. Clin Gastroenterol Hep 2004; 2:888-894.

Kaukinen K. et al. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol 2002; 97(3): 695-699.

Lundin, KE. HLA-DQ8 as an Ir gene in coeliac disease. Gut 2003; 52:7-8

Mazzarella G. et al. An immunodominant DQ8 restricted gliadin peptide activates small intestine immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut 2003; 52:57-62.

Sollid, LM and Lie, BA. Celiac disease genetics: Current concepts and practical applications. Clin Gastro Hep 2005; 3:843-851.

Wolters,VM and Wijenga C. Genetic background of celiac disease and its clinical applications. Am J Gastroenterol 2008; 103:190-195.

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Dr. Scot Michael Lewey
“Dr. Celiac, the food doc”
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