Celiac Disease - Genetic Variants and Predisposition

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Many different genes are involved in the pathogenesis of CD. Some of these genes encode proteins that function in the immune system, cell signaling, oxidative stress, and cell death (apoptosis), which all contribute to tissue damage in the intestine.

Genes that confer predisposition to CD

Two of the most important genes involved are found on chromosome 6, and are named HLA-DQA1 and HLA-DQB1.

Gene product

The two genes each encode part of a cell receptor protein (see Fig.1) that can bind molecules such as gluten. The receptor is made up of two different parts (A and B) and so is called a heterodimer.

          Heterodimer Definition: A protein complex formed by the linking of two subunits in which the subunits are of different protein compositions.


In the population, there are a number of slightly different versions of the genes HLA-DQA1 and HLA-DQB1. Each version, or variant, is called an allele. We inherit one chromosome 6 from our mother, and one chromosome 6 from our father. Therefore, we have two copies of HLA-DQA1 and two copies of HLA-DQB1, and for each gene, in a given individual, he or she may have two copies of the same allele, or one copy each of different alleles (e.g., HLA-DQB1*0201 and HLA-DQB1*0202). These different combinations of alleles make up different HLA-DQ heterodimer proteins (for example, HLA-DQ1 or HLA-DQ4).


There are two HLA-DQ combinations that especially increase an individual’s predisposition to CD. Ninety-five percent of people with CD have the heterodimer proteins DQ2 and DQ8. The DQ2 and DQ8 protein variants bind some gluten peptides more tightly, which helps provoke an immune response (see below). Having these alleles does not guarantee that one will get CD, because there are other genetic and/or environmental factors that also play a role in disease development.

What does the literature say?

The effect of having more than one copy of the HLA-DQ2 protein is controversial. Some studies suggest that having TWO copies (being homozygous) for a particular HLA-DQ2 allele (HLA-DQB1*02) might increase the severity of CD and increase the chance of developing refractory celiac disease, or enteropathy-associated T-cell lymphoma (EATL) (Karinen et al., 2006; Al Toma et al., 2006).

Another study (Bourgey et al., 2007) suggests that it might be possible to give parents an antenatal estimate of the “order of risk” of CD, through genetic evaluation of the parents’ HLA-DQ genes. The authors suggest that, “Specific follow-up can thus be offered for babies at high risk.”

Why doesn’t everyone with DQ2 or DQ8 get CD?

Although 40% of the US population has DQ2 and DQ8, CD is only present in approximately 1% of the population. Individuals with diabetes, autoimmune disorders, certain genetic syndromes, or close relatives with CD have a higher risk for developing the disease (Gujral et al., 2012). Simply having DQ2 or DQ8 and eating wheat, barley or rye, does not cause CD alone. This is because there are other environmental and genetic factors that contribute to the development of CD. One factor is control of permeability of the small intestine. For example, a virus infection in the gastrointestinal tract might cause intestinal inflammation, allowing gluten peptides to pass through the intestinal epithelial lining, leading to development of CD. There are also differences between antigen-presenting cells, T cells, B cells and “cellular signal molecules” of the immune system. Other gluten-related disorders add complexity to the diagnosis of CD, including gluten ataxia, dermatitis herpetiformis (DH), and non-celiac gluten sensitivity (NCGS). DH is a skin rash from manifestation of the small intestinal immune-mediated enteropathy precipitated by exposure to gluten in the diet. It responds to a gluten-free diet but may also require treatment with dapsone, a neutrophil inhibitor. NCGS is related to a number of immunological, morphological or other symptoms activated by consuming gluten in people when CD has been excluded (Ludvigsson, 2013).