Genetics

The association of coeliac disease with specific HLA types has long been known. While genetic testing in the diagnosis pathway for coeliac disease is not routinely recommended, it can have an important role in ruling out patients who will not likely (or never) require future testing for coeliac disease and may allow a risk assessment for those with the appropriate HLA types. 

The HLA system is on the short arm of chromosome 6, these are where the so-called disease association genes or permissibility genes are situated. 

HLA DQ2 and 8 typing is suggested in guidance as being helpful in excluding patients from future testing in at risk groups; first degree family relatives, and Down syndrome are some examples. In autoimmune conditions there are shared genetics between the conditions and in families there is a greater than by chance sharing of these permissibility genes.

Genetic studies have shown that in patients with coeliac disease, the commonest HLA DQ types are DQ2.5 (highest risk), followed by DQ8 (moderate risk) and then DQ2.2 (low risk, but not no risk). In patients (adults and children) who have coeliac disease, 99.6% of those patients will carry DQ2.5, 8 or 2.2.3 There are very rare patients who do not carry any of those three types. Although never a guarantee, being negative would be very reassuring. 

In addition to HLA typing, there are many other genes that have been looked at as candidates for factors that provide the extra risk but no firm conclusions have been made regarding their importance nor do we routinely test for them. 

The DQ2 and DQ8 haplotypes are found in up to 40% of the general population. The estimated prevalence of coeliac disease in the UK is 1% so there must be other factors that work with those HLA DQ haplotypes to cause the condition, given the right circumstances. HLA typing the general population is not recommended or currently practised. Current practise is to use it in specific clinical at-risk scenarios, primarily looking to exclude the condition. HLA typing is being explored in a population screening project in Italy.

HLA typing is widely available in the UK, but cost varies considerably from laboratory to laboratory and the format of the reporting is not standardised. Generally, such testing is through secondary care by paediatricians or gastroenterologists with an interest in coeliac disease or by specialist dietitians. 

Doing an HLA DQ type can be helpful in the following situations:

Patients on a gluten free diet without a diagnosis

A patient has gone on to a gluten free diet and finds symptoms are better. They may not have been tested for coeliac disease or may have been tested and found to be negative on standard serology antibody testing but due to symptoms they have gone gluten free. They then seek advice and ask the question – do I have coeliac disease? They are asked to reintroduce gluten but cannot tolerate it or they start a gluten challenge and due to clinical suspicion, the medical team perform the HLA typing as part of their investigations. Some patients may choose to do a commercial test and are looking for an explanation of the results. 

 A patient with suspected coeliac disease is not responding to a gluten free diet

In this case, if they test negative for DQ 2.5, 8 or 2.2 it could be stated with confidence that the patient does not have coeliac disease.

The patient tests positive for either DQ 2.5, 8, 2.2 or a combination of types 

This does not diagnose them as having coeliac disease. In this case it’s actually not very helpful, as so many of the general population are DQ positive and yet do not have coeliac disease. 

A child or young person with no symptoms but has an at-risk condition such as Type 1 diabetes tests positive for DQ 2.5, 8 or 2.2 

This does not diagnose them as having coeliac disease. All this really tells us is that they have the type that may permit them to have coeliac disease. This is where standard serology testing for the antibodies related to coeliac disease is important if they are on a gluten containing diet. If the antibody test is also positive, then it is likely they have coeliac disease, and some will need endoscopy and biopsy to confirm a diagnosis.