HLA-DQ7.5 and coeliac disease

Abstract

We have read with great interest the recently published UK NEQAS and BSHI guideline on laboratory testing and clinical interpretation of HLA genotyping results supporting the diagnosis of coeliac disease (CD) by Pritchard et al. (2023). Interpretation of HLA genotyping for CD can be challenging in clinical practice, and sometimes even misleading, and these proposed guidelines provide a valuable framework for standardizing HLA genotyping and its interpretation in the context of CD diagnosis. However, we would like to address a particular point of contention regarding excluding CD in patients expressing only HLA-DQA1*05 (in the form of DQ7.5) in the absence of HLA-DQ2.5, DQ8 and DQ2.2.

The guideline suggests that the presence of DQA1*05 alone (which occurs in HLA-DQ7.5), without the corresponding DQB1*02 allele to form the DQ2.5 heterodimer in cis or trans, should lead to the exclusion of CD (Pritchard et al., 2023). However, in our experience, coeliac patients expressing only HLA-DQ7.5 do exist, and among coeliac patients diagnosed at our centre are roughly as common as those with only DQ8 or only DQ2.2. More precisely at our centre we have diagnosed 6 DQ7.5⁺, 6 DQ2.2⁺ and 4 DQ8⁺ coeliac patients. This may seem strange at first, but it might be explained by the very high frequency of the DQ7.5 haplotype in the Italian general population (26%), whereas DQ2.2 is less common (15%) and DQ8 is quite rare (2%) (Margaritte-Jeannin et al., 2004). These figures differ significantly from those of other populations, as data show a HLA-DQ7.5 prevalence of 17% in France (Margaritte-Jeannin et al., 2004), 11% in a European American population (Megiorni et al., 2009) and 10% in Scandinavia (Margaritte-Jeannin et al., 2004).

Data in the literature also show that a small, yet significant, subset of coeliac patients express only HLA-DQ7.5. More precisely, estimates show that 0.3%–2.1% of coeliac patients carry only the DQ7.5 allele in the absence of DQ2.5, DQ8 and DQ2.2 (Erlichster et al., 2020; Fernández-Bañares et al., 2017; Karell et al., 2003; Margaritte-Jeannin et al., 2004; Megiorni et al., 2009; Schiepatti et al., 2021; Tinto et al., 2015). Moreover, in a large multicentric study on seronegative CD, DQ7.5 alone was also found among seronegative patients (Schiepatti et al., 2021). Therefore, although the risk conferred by DQ7.5 alone is indeed very low, it is not negligible and we think that DQ7.5 alone may not ‘automatically’ exclude CD. The exclusion of CD based on DQ7.5 could therefore lead to missed diagnoses in a small minority of coeliac patients carrying only DQ7.5, who could otherwise benefit from a gluten-free diet and appropriate management of their condition.

Given the potential clinical implications, we think that CD should not be excluded solely due to HLA typing showing DQ7.5 alone without DQ2.5, DQ8 or DQ2.2, and standard diagnostic testing for CD should performed, especially when symptoms suggestive for CD are present (Zingone et al., 2022).

Prof. Federico Biagi, MD