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    A practicing gastroenterologist in direct patient care but who also participates in teaching medical students and physicians in training as a Clinical Professor of Medicine at Rocky Vista University College of Osteopathic Medicine and at Kansas City University of Medicine and Biosciences. In addition to authoring peer review articles, book chapters and presenting clinical research Dr. Lewey has conducted, he has authored over 50 online articles, numerous blog posts and tweets about digestive and food related issues. As a physician who is a fellow of six professional societies Dr. Lewey serves at a national level on several committees, as a reviewer for journal articles and case reports, a media representative for the AOA Media and ACG on digestive health and disease and has been featured in various print, television, podcast and online media publications about digestive issues. As a expert in digestive diseases Dr. Lewey is also a medical legal consultant and expert witness. Dr. Lewey can be reached at Facebook.com/thefooddoc, on twitter @thefoodgutdoc and at www.thefooddoc.com, and his blog www.thefooddoc.blogspot.com.

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    Dr. Scot Lewey
    This article appeared in the Summer 2006 edition of Celiac.coms Scott-Free Newsletter.
    Celiac.com 08/31/2006 - All of us have patterns of proteins on the surface of our white blood cells. These proteins are known as human leukocyte antigens (HLA), one of which is DQ. Celiac disease 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 scientists 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 for 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 and 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 improved 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 indicated gluten sensitivity. This is consistent with the differences in prevalence rates of celiac disease seen in various parts of the world since DQ4 is not generally found in Caucasians 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 present in 90-99% of people who have celiac disease, are present in approximately 35-45% of people in the U.S., especially those of Caucasian race of Northern European ancestry, with highest risk of celiac disease but the prevalence in U.S. of celiac disease is 1%. Though a prevalence of 1 in 100 is very common and much higher than had been believed for years, only a fraction of the genetically at risk are confirmed to have celiac disease by abnormal blood tests and small intestine biopsies. However, the number of people who report a positive response to gluten-free diet is much higher.
    The stool antibody tests 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 responded to gluten-free diet. The strict criteria for diagnosing celiac disease, which is 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, though this cannot be said with 100% certainty especially since there are documented cases of celiac disease and the skin equivalent of celiac disease, known as dermatitis herpetiformis (DH) in individuals who are DQ2 and DQ8 negative.
    Therefore, knowing your DQ specific serotype pattern may be helpful for several reasons. For example, 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 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 that DQ7/DQ7 might be next highest risk. Dr. Fine has also noted some other associations of 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 but certain factors are believed to include 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 especially since several of those factors are associated with onset or unmasking of gluten sensitivity in someone who is at risk or not manifesting any recognizable symptoms. There is also well known group of individuals who are termed "latent" celiacs. They are 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 few or no symptoms but sometimes 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 appears 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 requires life-long complete gluten avoidance to reduce the increased risk of serious complications of undiagnosed and untreated celiac such as severe malabsorption, cancers, especially of the GI tract and lymphoma, other autoimmune diseases and premature death due to these complications.
    Again, DQ testing can be done with 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 by 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 panel includes genetic typing, stool testing for gluten and cows milk protein antibodies, and a test for evidence of malabsorption is $349.
    Again, the advantages of full DQ testing is determining if someone has more than one 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 risk for gluten sensitivity. If you determine all DQ types within enough family members you can piece together a very accurate history of the origin of celiac and gluten sensitivity within a family and make some very accurate predictions of risk 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. Fines 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. (Editors note: When present, these antibodies indicate celiac disease. However, they are not present in many cases of celiac disease.)
    In the meantime, many patients are faced with the uncertainty and added cost of full DQ testing and stool testing due to the failure of traditional blood tests, small bowel biopsies, and the presence or absence of DQ2 and DQ8 to diagnose or exclude gluten sensitivity. Physicians unfamiliar with this testing are increasingly presented with the results and confused or skeptical pending published reports. The medical community continues to lack a consensus regarding the definitions of non-celiac gluten sensitivity and what tests justify recommendations for gluten-free diet. It is clear that gluten sensitivity, by any criteria, is much more common than ever thought and a hidden epidemic exists.
    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, www.thefooddoc.com
    Article Source: EzineArticles.com

    Dr. Scot Lewey
    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 Sponsor: Review
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    The Glutenpro Celiac Genesure Genetic Test tests for the presence of the HLA DQ2 and HLA DQ8 genotypes.   A positive test means you are at risk for the disease, but it does not necessarily mean you will develop it.  A negative result means you do not have celiac disease and can never develop it. 
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    Jefferson Adams
    Celiac.com 03/02/2016 - A team of researchers recently completed the first extensive study comparing gene expression in children and adults with celiac disease, and found some key differences between the two groups.
    The research team included V. Pascual, L. M. Medrano , N. López-Palacios, A. Bodas, B. Dema, M. Fernández-Arquero, B. González-Pérez, I. Salazar, and C. Núñez. They are variously affiliated with Servicio de Pediatría, Servicio de Aparato Digestivo, and Servicio de Inmunología Clínica at the Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain, and with the Departamento de Producción Animal, Facultad de Veterinaria, and the Departamento de Estadística e Investigación Operativa I, Facultad de Matemáticas, Universidad Complutense de Madrid in Madrid, Spain.
    For their study, the team collected 19 duodenal biopsies of children and adults with celiac disease and compared the expression of 38 selected genes between each other, and in 13 non-celiac disease control subjects matched by age.
    The team used a Baysian methodology to analyze the differences of gene expression between groups. They found that, compared to controls, children and adults with celiac disease all had seven genes with a similarly altered expression. These were C2orf74, CCR6, FASLG, JAK2, IL23A, TAGAP and UBE2L3.
    The team found differences in 13 genes, six of which were altered only in adults (IL1RL1, celiac disease28, STAT3, TMEM187, VAMP3 and ZFP36L1) and two only in children (TNFSF18 and ICOSLG); while four genes show a significantly higher alteration in adults (CCR4, IL6, IL18RAP and PLEK) and one in children (C1orf106).
    Between the two groups, the team found significant differences in the expression level of several genes, most notably the higher alteration seen in adults.
    The team is calling for further research to assess possible genetic influences behind the changes, along with the specific physical consequences of the reported differences.
    Source:
    PLOS.ORG. Published: February 9, 2016. DOI: 10.1371/journal.pone.0146276

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