Celiac disease (CD) is a chronic autoimmune condition affecting the small intestine, triggered by consuming gluten, a protein found in wheat, barley, and rye. The immune system mistakenly attacks the body’s own tissues, making it distinct from a simple food allergy. Developing Celiac disease requires a specific genetic makeup, meaning the condition results from a complex interplay between inherited susceptibility and environmental triggers.
The Primary Genetic Location
The majority of the genetic risk for Celiac disease is concentrated on the short arm of Chromosome 6, specifically at region 6p21.3. This area houses the Human Leukocyte Antigen (HLA) complex, also known as the Major Histocompatibility Complex (MHC) Class II region.
The HLA complex includes genes that encode proteins on the surface of immune cells. These proteins present foreign invaders to T-cells to initiate an immune response, and specific variants here create a unique molecular environment that enables the autoimmune reaction to gluten.
The Specific Genes Involved
The genes within the HLA complex that confer susceptibility to Celiac disease are HLA-DQA1 and HLA-DQB1. These two genes work together to produce a single functional protein structure called an HLA-DQ heterodimer. The most common and highest-risk variants of this protein are known as HLA-DQ2 and HLA-DQ8.
Over 95% of Celiac disease patients worldwide carry one or both of these variants. The proteins they produce have a unique molecular shape highly efficient at binding to gliadin, a component of gluten. The HLA-DQ2 or HLA-DQ8 protein holds the gliadin fragment on the immune cell surface, effectively presenting it to T-cells.
This presentation initiates the cascade of events that leads to the autoimmune attack on the small intestine’s lining. The presence of these specific HLA variants is not the cause of the disease, but rather the necessary genetic hardware that allows the immune system to recognize gluten as a threat. Different combinations of the DQA1 and DQB1 alleles result in varying risk levels, with the HLA-DQ2.5 haplotype conferring the highest susceptibility.
Beyond the Main Genetic Markers
The presence of HLA-DQ2 and HLA-DQ8 genes is not sufficient to cause Celiac disease, illustrating incomplete penetrance. Carrying the susceptible genes does not guarantee the disease will develop. An estimated 30% to 40% of the general population carries these variants, yet only 1% to 3% of those individuals develop the condition.
This gap between genetic predisposition and actual disease development is explained by the disorder’s polygenic nature. Beyond the HLA region, scientists have identified more than 40 non-HLA genes spread across various chromosomes that also contribute to overall risk. These secondary genes often have small individual effects but cumulatively influence immune regulation and intestinal barrier function.
The combination of non-HLA genes with the primary HLA risk genes, alongside environmental factors like infections or changes in the gut microbiome, determines who develops the condition. While HLA genes account for the largest proportion of genetic risk, these additional genes help explain varying susceptibility, even among family members.
Genetic Testing and Risk Assessment
Genetic testing for Celiac disease focuses on identifying the presence or absence of the HLA-DQ2 and HLA-DQ8 genes. This testing is a powerful tool, particularly because of its high negative predictive value, which is greater than 99%. If a person tests negative for both the HLA-DQ2 and HLA-DQ8 variants, Celiac disease can be virtually ruled out as a potential diagnosis.
A negative genetic test can prevent the need for more invasive procedures, such as an endoscopy with a small bowel biopsy. This test is useful for screening first-degree relatives, who have a 1 in 10 risk of developing the disease, or for patients who have already adopted a gluten-free diet.
A positive genetic test result does not serve as a diagnosis for Celiac disease. Given that a large portion of the healthy population carries these genes, a positive result simply indicates a genetic susceptibility. Diagnosis requires subsequent serological blood tests for specific antibodies and, if necessary, a small bowel biopsy.