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

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‐GC...

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Published inJournal of pediatric gastroenterology and nutrition Vol. 77; no. 3; pp. 354 - 357
Main Authors Harris, R. Alan, Bush, Allyson H., Eagar, Todd N., Qian, Justin, Greenwood, Michael P., Opekun, Antone R., Baldassano, Robert, Guthery, Stephen L., Noe, Joshua D., Otley, Anthony, Rosh, Joel R., Kugathasan, Subra, Kellermayer, Richard
Format Journal Article
LanguageEnglish
Published Hagerstown, MD Lippincott Williams & Wilkins 01.09.2023
Subjects
Child
Crohn disease
Crohn Disease - complications
ERRalpha Estrogen-Related Receptor
Exome Sequencing
Genetic Predisposition to Disease
genetics
granuloma
Granuloma - genetics
Granuloma - pathology
Humans
inflammatory bowel disease
Mycobacterium
Phenotype
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Summary: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.
Bibliography:Dr Otley reports Advisory Board for AbbVie; research funding from AbbVie, Janssen, Takeda, Lilly, and Pfizer. The remaining authors report no conflicts of interest.
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Sources of Funding: This work was supported by the PRO‐KIIDS Network of the Crohn’s and Colitis Foundation [#585708 to RK]. We are grateful for philanthropic funds from the Wagner Family led Gutsy Kids Fund and the generous families contributing to that, and for funds from the Klaasmeyer family for PSC research to RK.
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Drs Harris and Bush contributed equally to the article.
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ISSN:0277-2116
1536-4801
1536-4801
DOI:10.1097/MPG.0000000000003873