Improved HLA-based prediction of coeliac disease identifies two novel HLA risk modifiers, DQ6.2 and DQ7.3
PurposeHuman Leukocyte Antigen (HLA) testing is useful in the clinical work-up of coeliac disease (CD), with high negative but low positive predictive value. We construct a genomic risk score (GRS) using HLA risk loci to improve CD prediction and guide exclusion criteria.\n\nMethodsImputed HLA genotypes for five European CD case-control GWAS (n>15,000) were used to construct and validate an HLA based risk models (HDQ15). Conditioning on this score, we identified novel HLA interactions which modified CD risk, and integrated these novel alleles into a new risk score (HDQ17).\n\nResultsA GRS from HLA risk allele genotypes yields performance equivalent to a state-of-the-art GRS (GRS228) using 228 single nucleotide polymorphisms (SNPs) and significantly improves upon all previous HLA based risk models. Conditioning on this model, we find two novel associations, HLA-DQ6.2 and HLA-DQ7.3, that interact significantly with HLA-DQ2.5 (p = 2.51 x 10-9, 1.99 x 10-7 for DQ6.2 and DQ7.3 respectively). These epistatic interactions yield the best performing risk score (HDQ17) which retains performance when implemented using 6 tag SNPs. Using the HDQ17 model, the positive predictive value of CD testing in high risk populations increases from 17.5% to 27.1% while maintaining a negative predictive value above 99%.\n\nConclusionOur proposed HLA-based GRS achieves state-of-the-art risk prediction, helps elucidate further risk factors and improves HLA typing exclusionary criteria, which may reduce the number of patients requiring unnecessary endoscopies.