Celiac Disease: Risk Alleles in the HLA-Genes - Typing of DQ2 and DQ8

Celiac disease, is a mal absorption disorder, caused by intolerance to gluten or related proteins in cereals such as wheat and rye. The immunological intolerance leads to a chronic inflammatory response in the small-intestinal mucosa with mal absorption syndromes like diarrhea, steatorrhea and loss of weight. Estimated prevalence rates in Europe range form 1 in 300 in Western Ireland to between 1 in 1000 and 1 in 2000 in other regions.

Susceptibility to gluten sensitivity is, at least in part, genetically determined. The incidence of celiac disease among first degree relatives has been estimated at 10-15%, among homozygous twin 70-100%. The strongest predisposition to celiac disease reported so far is associated with alleles at the HLA-DQ loci, that encode for the a and b chains of two MHC class II molecules .

DQ2 is possessed by 95% of all celiac patients

The DQ2 heterodimer which predispose for celiac disease is encoded by the DQA1*0501 and the DQB1*0201 alleles, the second predisposing heterodimer DQ8 is encoded by the DQA1*0301 and the DQB1*0302 alleles. DQ2 is possessed by 95% of all celiac patients compared to about 20% of controls. Thereby it makes no difference if this heterodimer DQ(a1*0501, b1*0201) is located on one chromosome in cis-position (haplotype DR3) or on the two homologous chromosomes in trans-position (haplotype DR7/DR5). The risk to an individual associated with the DQ(a1*0501, b1*0201) heterodimer is 50-fold increased over the average population risk.

Of the few celiac patients (less than 5%) who are negative for DQ(a1*0501, b1*0201), a great majority are positive for the second DQ-heterodimer DQ8, encoded by the DQA1*0301 and DQB1*0302 alleles. These patients often are HLA-DRB1*04 positive as well.

The DQ2 and DQ8 heterodimers may serve as a diagnostic marker for celiac disease as HLA-B*27 does for ankylosing spondylitis. In individuals with gastrointestinal malfunction, the presence of DQ2 and/or DQ8 would increase the chance that the person has celiac disease whereas the absence of this molecule would greatly argue against this assumption. In a recent European report, only 0.5% of celiac patients lacked both DQ2 and DQ8. As little as 0.3% of tissue transglutaminase autoantibody-positive individuals do not have DQ2 or DQ8. The majority of DQ2- and DQ8-negative celiac disease patients did in fact carry one half of the DQ2 heterodimer, often in the form DR7 (DQB1*0201).

HLA typing should be especially effective to identify individuals in celiac disease families with a high risk for the disease.

The prevalence of celiac disease has been significantly underestimated. The diagnosis currently rests on the histological demonstration of the characteristic lesion in the small intestine. Early diagnosis is important to start as soon as possible with a gluten-free diet. Untreated celiac disease often leads to other autoimmune disorders, such as type 1 diabetes (IDDM) or rheumatoid arthritis (RA).

Advantages of genotyping

In contrast to serological testing of autoantibodies against gliadin and related proteins the genotyping of predisposing alleles shows less false negative results. These false negative results often were causes by IgA-defiency, weak or less of enteropathy, as well as testing of children younger than 2 years. Nevertheless after a time of gluten-free diet, serological markers will turn to normal, so that molecular diagnostics are the only way to verify the diagnosis.

Nomenclature of the HLA-DR Alleles

The MHC class ll are cell surface molecules which perform an essential function in immunological detection on T-helper cells. They are encoded by the genes HLA-DR, -DQ and -DP.
Each MHC molecule is a heterodimer and consists of a a and a b chain. In the case of the DQ molecule, the a chain is encoded by the HLA-DQA1 and the b chain by the HLA-DQB1 gene. The genes HLA-DQA1 and HLA-DQB1 have a number of different alleles existing in a population, they are therefore polymorph.