Exome Sequencing Implicates DGKZ, ESRRA, and GXYLT1 for Modulating Granuloma Formation in Crohn's Disease.

Abstract

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn's disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing (WES) was performed on peripheral blood derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The CADD scoring tool was used to predict deleteriousness of SNPs. HLA haplotype findings were compared to a control group (n=8496). PLINK based analysis between GCD and NGCD groups did not find consistently significant hits. GnomAD control comparisons, however, showed consistent subgroup associations with DGKZ, ESRRA, and GXYLT1, genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.