HLA Genotyping
for Coeliac Disease

Epidemiology

Coeliac disease affects approximately 1% of the global population, and approximately 1 in 70 Australians have CD, with females being more commonly affected. Despite the rise in the prevalence and incidence of CD over time, only 20% of patients are diagnosed. Many patients remain undiagnosed or experience significant delays in diagnosis.

Clinical Presentation and Diagnostic Workup

CD diagnosis for patients on a gluten-containing diet is supported by a positive tissue transglutaminase serologic test but, in general, should be confirmed by a small bowel biopsy (gold standard diagnostic workup) showing the characteristic histology associated with CD.

Clinical manifestations of CD vary greatly according to age group. Diarrhoea and malabsorption are classic manifestations of CD; however, both children and adults can be paucisymptomatic and present extra-intestinal manifestations and systemic complications (Table 1). The National Institute for Health and Care Excellence (NICE) guidelines recommend testing for CD in patients presenting with classical and non-classical presentations, including chronic fatigue. An association between CD and autoimmune disorders and family history has been well documented (Table 1).

Table 1: Classical and Non-Classical Presentations and Indications for CD Testing

Genetic Disposition of CD

The main determinants for genetic susceptibility are the human leukocyte antigen (HLA) class II genes, particularly HLA-DQA1 and HLA-DQB1 genes encoding for HLA-DQ2 and HLA-DQ8 molecules, which are carried by almost all affected patients.

HLA susceptibility sets of alleles are expressed in a codominant manner. One set of alleles is inherited from each parent.

Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower-risk heterodimers (HLA-DQ8 or HLA-DQ2.2).

HLA "Gene-Dose Effect" and CD Relative Risk

HLA genotyping is considered a solid support in the diagnostic algorithm of CD. Unlike CD serology and intestinal histology, genotyping is a once-only test that is not reliant on gluten consumption for accuracy.

Both haplotypes, HLA-DQ2 and HLA-DQ8, encode molecules on antigen-presenting cells (APCs) that orchestrate the immune response to deamidated gluten, playing a crucial role in the development and pathogenesis of CD. The "gene dose effect" has implications on CD development and disease phenotype (Table 2). Compared to other heterodimers, HLA-DQ2.5 has the potential to bind and form strong complexes with the immune-dominant gluten peptides on APCs. Therefore, individuals with the HLA-DQ2.5 heterodimer have a higher risk of developing CD (Table 2).

Table 2: HLA Typing and Relative CD Risk

Recommendations for the Appropriate Clinical Use of HLA Typing in CD

The main utility of HLA typing is to assist with diagnostic risk stratification of CD. Due to a very high negative predictive value (NPV), a negative result for the HLA susceptibility genotypes virtually excludes CD. Positive results indicate CD risk, but it cannot confirm the diagnosis. Genetics alone do not cause the condition, as many people with these genes never develop CD. Supportive evidence with serology and diagnostic small intestinal biopsy is required.

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