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Genetics and coeliac disease

DQ typing - what’s the score?

The association of coeliac disease with specific HLA types has long been known. Over the last 20 years, the explosion of research into the inflammatory pathway and how it relates to specific HLA types has led to genetic testing becoming important in investigation strategies for the condition. Particularly in the diagnosis in children, HLA testing has been suggested recently as important 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. For anyone who has taken a look at the details of HLA typing, it can be very confusing and the relevance of the DQ2.2 type has been debated in depth.

In short, HLA DQ2 and 8 typing is suggested in guidance (ESPGHAN / BSPGHAN) as being helpful in excluding patients from future testing in at risk groups; first degree family relatives, Type 1 diabetes1 and Down's syndrome2 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. The utility of these guidelines is currently being road tested in a study called PRoCEDE (prospective coeliac disease evaluation) which is still to be reported.

The paper by Jason Tye-Din et al.3 summarises perfectly what we are looking for to either evaluate risk, or, if negative, rule out (almost completely) the condition for a patient and makes excellent suggestions as to how the results are reported.

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 2.2.4 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 risk5 but no firm conclusions have been made regarding their importance nor do we routinely test for them. We know that coeliac disease has major associations with other autoimmune conditions.

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 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 situation which is very common:

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.

The patient tests negative for all common HLA-DQ haplotypes.

A negative DQ 2.5, 8 or 2.2 would allow us to state with confidence that the patient does not have coeliac disease – this person is likely to be Non Coeliac Gluten Sensitive / Non Coeliac Wheat Sensitive.6

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 is a similar scenario to the one above where the patient tested positive. All this really tells us is that they have the type that may permit them to have coeliac disease. This does not tell us that they have coeliac disease. Clearly 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 the majority will need endoscopy and biopsy to confirm a diagnosis.

A publication by Paul et al.7 reports on three cases studies where HLA-DQ testing was used when not indicated.

For more information on genetics and coeliac disease which you can share with your patients, please visit this web page.

References

1. Mitchell RT, et al. Arch Dis Child 2016; Mar;101(3):230-3. doi: 10.1136/archdischild-2015-309754

2. Sumner C, et al. Arch Dis Child 2016; 101: Suppl 1 A215-A216 doi:10.1136/archdischild-2016-310863.358

3. Tye-din J, et al. Intern Med J 2015; Apr;45(4):441-50. doi: 10.1111/imj.12716

4. Karell K, et al. Hum Immunol 2003; Apr;64(4):469-77

5. van Heel DA, et al. Nat Genet 2007; Jul;39(7):827-9

6. Sapone A, et al. BMC Med 2012; Feb 7;10:13. doi: 10.1186/1741-7015-10-13

7. Paul SP, et al. Scott Med J 2017; Jan 1:36933016689008. doi: 10.1177/0036933016689008. [Epub ahead of print]

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