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

Authors

R Alan Harris
Allyson H Bush
Todd N Eagar
Justin Qian
Michael P Greenwood
Antone R Opekun
Robert Baldassano
Stephen L Guthery
Joshua D Noe
Anthony Otley
Joel R Rosh
Subra Kugathasan
Richard Kellermayer

Publication Date

9-1-2023

Journal

Journal of Pediatric Gastroenterology and Nutrition

DOI

10.1097/MPG.0000000000003873

PMID

37347142

PMCID

PMC10528115 D

PubMedCentral® Posted Date

9-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Child, Humans, Crohn Disease, Exome Sequencing, Genetic Predisposition to Disease, Granuloma, Phenotype, ERRalpha Estrogen-Related Receptor, granuloma, genetics, inflammatory bowel disease, Mycobacterium

Abstract

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing 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 (a tool set for whole-genome association and population-based linkage analyses) 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 Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (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.