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

Author:

Harris R. Alan1,Bush Allyson H.2,Eagar Todd N.34,Qian Justin2,Greenwood Michael P.34,Opekun Antone R.2,Baldassano Robert5,Guthery Stephen L.6,Noe Joshua D.7,Otley Anthony8,Rosh Joel R.9,Kugathasan Subra10,Kellermayer Richard211

Affiliation:

1. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX

2. Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX

3. Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX

4. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY

5. Division of Gastroenterology, Hepatology and Nutrition, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA

6. Department of Pediatrics, University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT

7. Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI

8. IWK Health/Dalhousie University, Halifax, Nova Scotia, Canada

9. Goryeb Children’s Hospital/Atlantic Children’s Health, Morristown, NJ

10. Departments of Pediatrics and Human Genetics at Emory University School of Medicine, Atlanta, GA

11. Children’s Nutrition and Research Center, Houston, TX.

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.

Publisher

Wiley

Subject

Gastroenterology,Pediatrics, Perinatology and Child Health

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