Multi-Omics Assessment of Genetic Risk for Celiac Disease in Down Syndrome

Abstract

ABSTRACTObjectivesIndividuals with Down syndrome (DS) display high risk of celiac disease (CD), but the mechanisms underlying this increased susceptibility await elucidation. Here, we examined the prevalence of HLA genotypes associated with CD risk in the general population and tested a previously developed genetic risk score (GRS) for CD in people with DS.MethodsHLA genotypes were obtained for 204 individuals with DS in the Human Trisome Project cohort study, of whom 9% had CD. We compared HLA genotype frequencies in those with and without CD against frequencies observed in the general population. CD permissive HLA haplotypes explored were DQ2.5, DQ2.2, DQ8.1, and DQ7.5. We also analyzed 38 non-HLA-DQ alleles used to generate the CD GRS.ResultsFrequencies of risk genotypes were different for CD in DS versus CD in the general population. For example, we observed lower frequency of DQ2.5/DQ2.5 and higher prevalence of DQ7.5/X and X/X in CD in DS. Although GRS values were significantly increased in those with CD and DS, their predictive power was decreased relative to the general population. Transcriptome analysis revealed dysregulated expression of many genes composing the GRS in DS. Proteomics analysis showed that GRS values correlate with elevation of specific immune factors in DS.ConclusionsThe genetic risk profile of CD in DS is different relative to the general population, which is likely due to dysregulation of immune pathways in DS. Larger studies are needed to elucidate pathogenic mechanisms and to develop a validated GRS for CD in DS.What is KnownCeliac disease is more common in individuals with Down syndrome, but the impact of HLA risk genotypes in this population is unclear.A celiac disease genetic risk score incorporating HLA-DQ and non-HLA SNPs has been developed with good predictive accuracy in the general population.What is NewIndividuals with DS may still develop CD even without the traditional HLA-DQ risk factors.A modified CD genetic risk score may be applied to individuals with DS with good accuracy and specificity.The immune dysregulation characteristic of DS involves dysregulated expression of many genes involved in CD etiology.