Genetics in the Diagnosis of Celiac Disease: Role of HLA DQ2 and DQ8
المؤلف:
Marcello Ciaccio
المصدر:
Clinical and Laboratory Medicine Textbook 2021
الجزء والصفحة:
p493-494
2025-12-09
117
The genetic background is a necessary condition for the development of the disease in both the classic clinical forms and the latent and silent forms. The main genetic factor pre disposing to celiac disease is the HLA DQ2 haplotype (DQA1*0501-DQB1*0201), which is expressed in 90% of patients affected by the celiac condition, while the DQ8 haplotype (DQA1*0301-DQB1*0302) is expressed in 5% of patients and the remaining 5% are carriers of at least one of the two DQ2 allies (usually DQB1*0201). In a very concise manner, it can be stated that approximately 70–75% of the population is not a carrier of DQ2 or DQ8 and, therefore, has very little, if any, chance of suffering from the celiac condition. Of the remaining 25–30% of the population who are carriers of DQ2 or DQ8, only 4% will develop the disease. Therefore, the presence of the DQ2 or DQ8 haplotype identified by a positive genetic test is a necessary, but not sufficient, condition for diagnosing the celiac condition.
HLA DQ2/DQ8 molecules are expressed in the dendritic cells of the gut mucosa and have high affinity for deamidated gliadin peptides; the binding between DQ2/DQ8 and deamidated peptides is the basis of the immune response as gluten- derived antigens are exposed to T cells that trigger the pathological process of autoimmune response; this is the rea son for the importance of the HLA DQ2/DQ8 genetic configuration.
HLA class II includes not only DQ2 and DQ8 but a wide variety of possible alleles, many of which are involved in susceptibility to autoimmune diseases or, in some cases, are protective. HLA enters the major histocompatibility com plex (MHC) locus on the short arm of chromosome 6, where several genetic regions are located; the one of interest in celiac disease is the class II region, which contains a number of genes, including HLA DQB1 and HLA DQA1, which are in linkage with the DR locus. The A1 gene encodes for the α protein chain, the B1 for the β protein chain; in antigen- presenting cells, these proteins are expressed at the mem brane level to form a heterodimer. About DQ2, the most important allele is *02 of the DQB1 locus, which encodes the β chain of the HLA DQ2 heterodimer. For the presence of DQ2 for the expression of celiac disease, it is necessary to have this allele. However, it is not sufficient: it is also necessary to have the *05 allele of the DQA1 locus. These alleles can be combined in a very variable and complex way. For DQ8, the combination of the *0302 allele from the DQB1 locus and the *03 allele from the DQA1 locus is required. Many techniques, now routine in the molecular biology laboratory, are available to perform HLA DQ2/DQ8 analysis. For example, an allele-specific PCR can be performed with analysis by agarose gel electrophoresis, or sequencing can be performed. In reality, however, the goal is to detect only the possible presence of the four alleles directly involved. One of the possible methods is a real-time PCR analysis, using specific sequences, primers and probes that recognize the alleles of interest. The DNA sample is analyzed, and if the main allele (*02 of the DQB1 locus) is detected, an amplification signal is detected. In order to confirm that the subject is positive for HLA DQ2, it is then necessary to detect also the *05 allele of the DQA1 locus, using the same method. It is then possible to verify if *02 of the DQB1 locus is in homozygosity or in heterozygosity. If the result is positive, the various allelic combinations translate into a different risk of disease. In fact, it is a different condition to have all the DQ2 and DQ8 alleles expressed compared to having only *02 of the DQB1 locus.
As far as family members are concerned, who are individuals at risk, there is debate in the scientific community about the advisability of carrying out the genetic test: If it is negative, the celiac condition can be excluded, and this is a reason for supporting the advisability of the test. However, the probability that family members of celiacs have this haplotype and that the test is positive is very high, and in this case, there is nothing that can be done to prevent the disease. The problem, therefore, is to translate the different risk associated with the results of the genetic analysis into clinical practice. There are many other genes other than the HLA genes mentioned above that play a role in the predisposition to celiac disease and other autoimmune diseases, but each non-HLA variant makes a minimal contribution to the genetic risk associated with HLA; therefore, it is difficult to think of analyzing all the variants, and, in any case, their clinical significance is not particularly relevant.
In conclusion, with regard to the diagnosis of celiac dis ease due to genetic predisposition, it can be concluded as:
• The HLA locus is the main genetic predisposition factor for celiac disease.
• The presence of the HLA DQ2 and DQ8 haplotypes is necessary, but not sufficient for the development of the pathology.
• The absence of HLA DQ2 and HLA DQ8 allows the exclusion of celiac disease, and these patients do not require further testing over time for suspected celiac disease.
• There is a risk gradient for celiac disease associated with the different HLA DQ haplotypes that are derived from various combinations of the HLA DQA1 and DQB1 alleles.
• The conclusive diagnosis of celiac disease in symptomatic children is made if there is the simultaneous presence of HLA DQ2 or DQ8 with IgA class antitransglutaminase levels greater than 10 times the threshold used by the laboratory.
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