Questions and answers on HLA typing and Celiac Disease

Copyright by Michael Jones, Bill Elkus, Jim Lyles, and Lisa Lewis 1995, 1996 - All rights reserved worldwide.

Disclaimer

This file is a summary of various posts made on the CELIAC List about genetics and celiac, and more specifically about HLA typing in Celiac Disease. It has been supplemented by private E-Mail with various experts in this area of CD, and has been reviewed for technical accuracy by Drs. Ludvig Sollid (University of Oslo) and Karoly Horvath (University of Maryland), two of the CEL-PRO experts. This file is formatted as a question and answer session.


Table of Contents

  • What are the basic statistics on the risk of Celiac Disease amongst the general population?
  • What are the basic statistics on the increased risk of Celiac Disease among the various relatives of a diagnosed celiac?
  • Can genetics testing determine if my sibling will get Celiac Disease?
  • How common are the Celiac-related HLA markers in the general population? In other words, how specific to Celiac Disease are the Celiac-related HLA markers?
  • If HLA testing only shows tendencies, why bother doing it at all?
  • What does HLA mean?
  • How does one test for HLA markers? Where? How much does it cost? Will insurance cover it?
  • How many different types of HLA markers are there?
  • Which HLA markers are associated with Celiac Disease? I have been confused, sometimes reading about DQ2, at other times about DR3, B8 and other markers.
  • If one has two copies of the Celiac-related markers instead of one, does it make a difference?
  • Are there non-HLA genes involved in determining if someone has the potential to get Celiac Disease?
  • Are there any known HLA or other genetic markers associated with gluten intolerance in autism?
  • What other disorders is a Celiac more susceptible to due to genetics (as opposed to intestinal damage and/or malabsorption)?
  • Could my family's genetics be used to advance the scientific knowledge in this area? If so, then who should I contact?
  • Can you give me some references to read or show my doctor for further details?
  • Internet references:

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    What are the basic statistics on the risk of Celiac Disease amongst the general population?

    For reference purposes it would be helpful to know the rate of Celiac in the general population. In America, this rate is unknown but based upon their 1995 study on random samples of blood-bank blood, Drs. Fasano and Horvath suspect it is around 1 in 250 (0.4%). This is about the same rate as seen in Europe amongst populations where large samples of people have been carefully studied, and the latent and asymptomatic cases of CD have been counted.

    Some people have had the notion that Celiac was almost totally absent in African-American and Asian populations, however clinical observations and some studies of immigrants who have added gluten-containing foods have shown surprising rates of Celiac. Therefore it is unclear if the historical low reported rates of CD were due to lack of gluten, lack of proper diagnosis, or lower genetic susceptibility.

    Additional information on CD in these populations can be found at:

    (a) Brueton & al Coeliac disease in Asian children in United Kingdom: in McConnell RB (ed): The Genetics of Coeliac Disease. Lancaster, MTB Press, 1981, pp. 103-108

    (b) Sher & al. High risk of coeliac disease in Punjabis. Epidemiological study in the South Asian and European Populations of Leicestershire. Digestion 1993; 54: 178-182).

    (c) Boudraa et al. Epidemiology of gluten intolerance in North Africa. In: Common Food Intolerances. I.: Epidemiology of Celiac disease. Dyn. Nutr. Res., Basel, 1992. vol.2, pp 64-70.

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    What are the basic statistics on the increased risk of Celiac Disease among the various relatives of a diagnosed celiac?

    The overall familial prevalence of Celiac Disease is approximately 10% in first degree relatives of a diagnosed celiac. First degree relatives include the parents, siblings, and children. Both Dermatitis Herpetiformis and Celiac Disease may be seen in the same family. (The closer the relationship of the affected person, the higher the risk.) The term "concordance" below refers to how often CD is found amongst two people with a specified relationship. The highest concordance is amongst identical twins (70%), HLA identical siblings (30-40%) and siblings sharing just one DR3 marker (20-30%), with other non-HLA identical siblings much lower (0-10%). The rates differ depending on which genetic study one refers to.

    The fact that identical twins do not always both get CD implies that there are both genetic and non-genetic factors involved. The non- genetic factors are not yet known. Certain viruses or stress triggers are suspected. The fact that there is a difference in the risk factors between identical twins (70%) and HLA-identical siblings (30-40%) implies that there are also non-HLA genetic factors involved.

    Even if there are no obvious gastrointestinal symptoms, some gastroenterologists recommend that all first degree relatives of a Celiac get endomysial antibody blood tests, which are over 90% predictive of whether a biopsy will be positive. If the test is negative, it is often recommended that first degree relatives get retested 2-5 years in the future, or if symptoms associated with Celiac Disease (or unexplained symptoms) ever develop.

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    Can genetics testing determine if my sibling will get Celiac Disease?

    No, but it can give you a great deal of insight into the probability of developing Celiac Disease. If your sibling does not have the HLA markers associated with CD, it is extremely unlikely that he/she will ever develop the disorder. However, if he/she does have these markers, there is currently no way of predicting whether or not the disorder will eventually develop. It is known that the risk of CD is vastly increased (about 50-100 times more likely than in the general population) in these siblings.

    It appears that HLA types are not the complete, final answer on the genetics of CD. Periodically, CD patients are found who do not carry any of the known HLA risk factors which we will be discussing in this file. Thus, Celiac is a multifactorial disorder with very strong (but not exclusive) association with a few HLA factors.

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    How common are the Celiac-related HLA markers in the general population? In other words, how specific to Celiac Disease are the Celiac-related HLA markers?

    We will go into more detail soon, but generally speaking, about 25-30% of the general population of European extraction has these particular HLA markers. These same markers are found in more than 95% of all Celiacs.

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    If HLA testing only shows tendencies, why bother doing it at all?

    This is an excellent question. Many gastroenterologists do not recommend HLA typing of the family members of a Celiac. The following are the reasons that one might do it anyway:

      a) Excluding CD as possibility. If a person has been having symptoms which may be indicative of CD, but the serology or biopsy are inconclusive, then HLA typing can be done as another data point. Although it is not a "specific" test, since 25-30% of those without CD will carry the CD-associated markers anyway, it can be helpful to exclude CD in those who are found to not be carrying the HLA markers.

      b) Necessity of serology re-testing. Dr. Horvath recommends that every person in the immediate family of a Celiac have endomysial / reticulin / gliadin serology testing, even if no obvious Celiac-type symptoms exist. Even if the test is negative, he recommends re-testing every two to five years, in case CD develops in the future. If you have had HLA typing, and know that you do not have the HLA markers associated with Celiac Disease, then it should not be necessary to have the Celiac blood tests in the future.

      c) Attention to at-risk siblings. The flip-side of "b" above is that if you know a sibling is "at risk" for CD due to HLA typing, then you may be more attentive to the development of symptoms suggestive of CD in the future. This may result in seeking medical help more quickly and reducing the damage done by undiagnosed CD.

      d) Delay the introduction of gluten to 'at risk' children. A controversial use of HLA typing would be to change the diet before any symptoms or positive serology occur. HLA typing can easily be done on the umbilical cord blood at birth. If your newborn is found to carry the markers associated with CD, you may consider not introducing gluten into the diet for several years. To our knowledge, there is no evidence whatever that this will reduce the chance of CD in the future. However, if CD does develop, it could be less of a factor in the overall physical and mental development of the child. Infants and toddlers have rapidly developing nervous systems and infrastructure, and it would seem that Celiac Disease would be especially disruptive at a very early age.

    In addition, there is some evidence that gluten intolerance may be a strong factor in the development or aggravation of certain developmental disorders, such as autism. These disorders typically develop during the first 2-3 years of life. When checking for the HLA markers for increased risk of Celiac, families at risk for autism might also check to see if their infant has any of the HLA markers associated with an increased risk for autism (for more information on this topic, send an E-Mail to listserv@LISTSERV.ICORS.ORG with the body:

    GET CELIAC HLA-WAR1
    GET CELIAC HLA-WAR2

    If gluten is added after language and social interaction have become well-developed, it may dramatically reduce the probability of developing these disorders. While no data has been published to support this theory, those with an autistic child in the family can attest that maintaining a gluten-free diet is much less difficult than the problems associated with autism in general.

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    What does HLA mean?

    HLA stands for Human Leukocyte Antigen which are certain molecules found on the surface of cells. More than 100,000 HLA molecules (many copies of some few variants; see below) can be expressed on the surface of a single cell. The genes which encode (i.e. determine the structure of) these HLA molecules are found on Chromosome 6 in humans.

    HLA molecules are involved in immune regulation. They bind to small fragments(peptides) of bacteria, virus etc. and present these to particular cells (T-cells) of the immune system. T-cells patrol the body and are educated to inspect whether the HLA molecules display peptides that are foreign to the body. If a T-cell recognizes something foreign, it sends out an "alarm". This will result in an immune response and the immune system will start to attempt to defeat the presumed intruder in the body. It is likely that in Celiacs the immune system reacts to gluten and that the immune response which is initiated in the small intestine on contact with gluten results in alterations of the normal gut tissue.

    Why only some individuals react to gluten is not completely understood. There exist a large number of different variants of HLA molecules. Which HLA molecules an individual manufactures is determined by the gene-variants the individual has inherited from his or her parents. It is conceivable that some particular varieties of HLA molecules (i.e. DQ2 and DQ8; see later) are particularly efficient in binding and presenting gluten fragments and that individuals who carry these particular HLA molecules are more prone to develop Celiac Disease. It is important to remember that the very same HLA molecules that present gluten fragments also are very efficient in presenting fragments of virus and bacteria and are thus of great importance for the body to survive from various infections.

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    How does one test for HLA markers? Where? How much does it cost? Will insurance cover it?

    HLA typing can be done either by analyzing the genes which code for the HLA molecules or by analyzing the HLA molecules themselves. Today most laboratories perform HLA typing by analyzing the HLA molecules on the surface of cells. Conveniently the typing is done with leukocytes (white blood cells) that are isolated from a blood sample. In some few years gene-analysis may become the standard way of doing HLA typing.

    Most large commercial laboratories can perform HLA typing. The cost varies, depending on where it is performed, and how many HLA markers are specified to be analyzed. The costs range from $160 to $800 in the few examples the Listowners have seen. Those who donate blood for celiac genetics studies typically get the HLA typing done for free.

    Not only will insurance generally NOT cover HLA typing (at least in the US), but some patients are fearful that if their insurance company discovers that they have HLA markers implying a much higher risk for developing a serious disease, that in the future, coverage may be denied. This is topic on which heated discussion is occurring in the U.S. Some patients actually use a different doctor for their HLA typing and do not submit the invoice to their insurance company for this reason.

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    How many different types of HLA markers are there?

    Your HLA type can be called your body type just as your particular ABO type is your blood type. HLA terminology is rather complex. To make matters worse, the coding has been changed several times by the immunologists. The following is an attempt to explain the HLA system in a simplistic way:

    HLA molecules exist in two classes. HLA-A, HLA-B and HLA-C molecules make up the class I molecules and HLA-DR, HLA-DQ and HLA-DP molecules make up the class II molecules. All HLA molecules consist of two units; an alpha chain and a beta chain. For each chain there is a corresponding gene. The genes coding for HLA molecules (except the gene coding for the beta chain of class I molecules) are positioned on a stretch of chromosome 6 like pearls on a string. For each gene locus (each position) there exist a large number of variants or alleles (colors of pearls). For some loci there are more than 100 different variants described! Each individual has two chromosomes (pearl strings) which are inherited from the mother and the father. The composition of alleles on the two chromosomes (combination of colored pearls on the strings at different positions) are characteristic for each individual. Typically, the genes of one chromosome (the colored pearls on one string) code for one HLA-A molecule, one HLA-B molecule, one HLA-C molecule, two HLA-DR molecules, one HLA-DQ molecule and one HLA-DP molecule. Provided that the genes on the individual's two chromosomes code for different variants (i.e. there are different color of the pearls in the corresponding positions on the two strings) an individual may express as much as 14 different HLA molecules. (The number can be larger as in some instances alpha- and beta-chains of HLA-DQ and HLA-DP molecules that are coded for by genes on opposite chromosomes may form functional molecules).

    Which alleles (color of pearls) that occur together at the various loci (positions) are not completely random. Some combinations are particularly frequent. Several combinations of alleles (color of pearls) are usually maintained together as gene blocks (segments of pearls). If you have one particular allele (color of pearl) at one locus (position) you very often have another distinct allele (color of pearl) at a neighboring locus (position). This phenomena is termed linkage disequilibrium and is very important for understanding association of certain diseases with particular HLA markers.

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    Which HLA markers are associated with Celiac Disease? I have been confused, sometimes reading about DQ2, at other times about DR3, B8 and other markers.

    The three markers DR3, B8 and DQ2 are all associated with Celiac Disease. The reason for this is that the genes which code for B8, DR3 (also termed DRw17) and DQ2 are in linkage disequilibrium. They are part of a gene segment that is usually maintained as a gene block. This fact has posed a problem in the work to identify which molecules are actually involved in the development of Celiac Disease and which alleles are just associated with CD because the genes coding for these molecules are usually linked with the predisposing genes. In other words: Which of B8, DR3 or DQ2 are actually involved in the development of Celiac Disease and which are just marker molecules?

    Those Celiacs who are not DR3 positive very often are DR5/DR7 (DR5 is coded for by genes on the one chromosome and DR7 is coded for by genes on the other chromosome). Individuals who are DR3, almost always also are DQ2 (because the genes coding for DR3 and DQ2 are in linkage disequilibrium - they are in a conserved gene block). The names of the genes in this gene block that jointly code for DQ2 are DQA1*0501 (which codes for the alpha chain) and DQB1*02 (which codes for the beta chain). The DQA1*0501 gene also exists in a gene block that contains the gene coding for DR5, and the DQB1*02 gene exists in a gene block that contains the gene coding for DR7. Individuals who are DR5/DR7 may thus also possess the DQA1*0501 and DQB1*02 genes. In contrast to individuals who are DR3-DQ2 the DQ genes in DR5/DR7 individuals which code for DQ2 are located on two different chromosomes. This explains why DR5/DR7 individuals also have a predisposition to develop Celiac Disease and strongly indicates that it is DQ2 coded for by the DQA1*0501 and DQB1*02 genes that actually are involved in the development of Celiac Disease. About 95% of the Celiac population carry these particular genes.

    In addition, another 4-5% of the Celiac population have genes that code for DR4 and DQ8 molecules (the genes coding for DR4 and DQ8 are maintained in block of genes). Probably it is the DQ8 molecule that mediates the disease predisposition in this subgroup of patients. Some very few Celiacs are neither DQ2 nor DQ8 implying that HLA typing is not a perfect predictor of risk for Celiac Disease.

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    If one has two copies of the Celiac-related markers instead of one, does it make a difference?

    Recent results indicate that individuals who carry the DQA1*0501 and DQB1*02 alleles and in addition have an extra copy of the DQB1*02 allele have an increased risk of developing Celiac Disease. This is called a "gene-dosage effect". The DR types of individuals who usually carry these DQ genes are DR3/DR3 (i.e. DR3 homozygous) and DR3/DR7.

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    Are there non-HLA genes involved in determining if someone has the potential to get Celiac Disease?

    Probably. The fact that there is a difference in the risk factors between identical twins (70%) and HLA-identical siblings (30-40%) implies that there are probably non-HLA genetic factors involved. Research on this topic is continuing.

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    Are there any known HLA or other genetic markers associated with gluten intolerance in autism?

    Not much has been published on this topic. Dr. Reed Warren of Utah State University has published several studies on the genetics of autism in Northern Utah. Those studies did not show a significantly increased prevalence of DR3 in autism. Gene Stubbs of Ohio State University has stated in unpublished correspondence that he found substantially increased DR3 in the parents of autistic children.

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    What other disorders is a Celiac more susceptible to due to genetics (as opposed to intestinal damage and/or malabsorption)?

    There are many autoimmune disorders where, as in Celiac Disease, certain HLA markers on chromosome 6 are associated with a far higher risk for the disorder. To obtain a copy of an autism article by Dr. Reed Warren, where the introduction maps out which disorders are associated with various HLA markers, send GET CELIAC HLA-TYPE in the body of an E-Mail to: listserv@LISTSERV.ICORS.ORG.

    Any disorder which is linked with DR3 is likely to be found more often amongst Celiacs than amongst the general population. By far the most well known such disorder is Type I ("juvenile") diabetes. Diabetics are almost always associated with either DR3 or DR4. Therefore, every diabetic should realize that they have a much higher risk of having, or developing, Celiac Disease than the general population. And Celiacs should realize that they may have a higher risk of developing Type I diabetes than the general population.

    Other disorders which have been claimed to be associated with DR3 include: Grave's disease, Addison's disease, Sjogren's syndrome and Systemic Lupus Erythematosus. Reference: Rose et al, Manual of Clinical Laboratory Immunology, 4th Edition (1992), American Society for Microbiology, Washington DC.

    Finally, those with Down's Syndrome have been reported to have both an increased risk for CD, and also an increase in gluten-sensitivity (but not Celiac Disease itself). See:

      (a) Reichelt K & al. Acta Paediatrica Japonica (1994) 36, 489-492.

      (b) Zubillaga P & al. Down's syndrome and Celiac Disease. J. Ped. Gastroenterol. Nutr. 1993: 16, 168-171.

      (c) Castro M & al. Down's syndrome and Celiac Disease: The prevalence of high IgA-antigen antibodies and HLA-DR and DQ antigens in trisomy 21. J. Ped. Gastroenterol. Nutr. 1993: 16, 265-268.

      (d) Hilhorst MI & al. Down syndrome and coeliac disease: Five new cases with a review of the literature. Eur. J. Pediatr 1993: 152, 884-887.

      (e) Janson U. & Johansson, C. Down Syndrome and Coeliac Disease. J. Ped.Gastroenterol. Nutr. 1995: 21, 443-445.

      (f) Nowak et al. Celiac sprue in Down's syndrome: Considerations on a pathogenetic link. Am J Gastroenterol 1983; 78: 280-283.

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    Could my family's genetics be used to advance the scientific knowledge in this area? If so, then who should I contact?

    From time to time, posts are made to the Celiac List asking for research volunteers. Geneticists are particularly interested in finding families with at least two Celiacs in the same immediate family. Contact one of the Listowners for a referral to a professional involved in current research.

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    Can you give me some references to read or show my doctor for further details?

      The following journal article is a comprehensive summary of current genetic research in Celiac Disease: HLA Susceptibility Genes in Celiac Disease: Genetic Mapping and Role in Pathogenesis. Sollid and Thorsby, Gastroenterology 1993; 105: 910 - 922.

      There was an excellent medical textbook 'Coeliac Disease' edited by Michael Marsh and published in 1992 by Blackwell Scientific (ISBN 0-632-03097-6). This book covers many Celiac subjects in great detail, and has several chapters on genetics. Its main disadvantage is its price (over $200) but some medical libraries carry it.

      Another recent review: P.D. Howdle in Bailliere's Clinical Gastroenterology Series Vol 9 No 2 1995 (ISBN 0-7020-1953-4). The book has a section by Tighe & Ciclitira entitled: The gluten - host interaction which also deals with HLA association In Celiac Disease.

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    Internet references:

    From a database of articles on Mendelian Inheritance in Man from the National Center for Biotechnology Information (Johns Hopkins U.). This page has a good detailed discussion of the genetics of celiac disease:

      http://www3.ncbi.nlm.nih.gov:80/htbin-post/Omim/dispmim?212750

    They also have a page on DH:

      http://www3.ncbi.nlm.nih.gov:80/htbin-post/Omim/dispmim?601230

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    This fact sheet has been designed to be a general information resource. However, it is not intended for use in diagnosis, treatment, or any other medical application. Questions should be directed to your personal physician. This information is not warranted and no liability is assumed by the author or any group for the recommendations, information, dietary suggestions, menus, and recipes promulgated. Based upon accepted practices in supplying the source documents, this fact sheet is accurate and complete. Products mentioned or omitted do not constitute endorsement.

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