Phenome-wide association study in adult coeliac disease: role of HLA subtype.

Abstract

Coeliac disease arises in genetically susceptible individuals, in particular in carriers of HLA-DQ2/DQ8 risk alleles and is associated with various comorbidities. Coeliac disease may confer an increased mortality, but the data are conflicting. We aimed to characterize mortality and morbidity in patients with coeliac disease with a special focus on the role of the number of HLA risk alleles. We studied coeliac disease-associated morbidity and mortality in ~500000 participants of the UK Biobank including 2482 individuals with the diagnosis of coeliac disease. We used an unbiased, multivariable Phenome-Wide Association Study (PheWAS) method to uncover the coeliac disease-associated disorders. The tag SNP approach was used to divide the coeliac disease subjects into HLA-DQ2/DQ8-based risk categories. We found 225 ICD-10 codes significantly associated with coeliac disease. During the median follow-up of 10.7years, coeliac disease individuals (n=2482) had higher overall mortality (HR 1.6 [95% CI, 1.4-1.8]) than controls and both an increased occurrence of and an increased mortality from cancer, respiratory and cardiovascular diseases (HR 1.4-1.6). Coeliac disease individuals with 2 HLA-DQ2/8 risk alleles had a similar overall mortality as coeliac disease participants with 0-1 HLA-DQ2/8 alleles, but were more likely to die from lymphoproliferative diseases (HR 7.6 [95% CI, 1.01-57.25]). Our data suggest that the increased mortality from lymphoproliferative diseases is restricted to those coeliac patients with 2 HLADQ2/8 alleles and that a combination of coeliac disease and HLADQ2/8 alleles is needed to increase the susceptibility. Once confirmed, closer monitoring may be warranted in this high-risk subpopulation.