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Genetic Risk for Inflammatory Bowel Disease Is a Determinant of Crohn's Disease Development in Chronic Granulomatous Disease

Huang, Chengrui PhD; De Ravin, Suk See MD; Paul, Adam R. DO; Heller, Theo MD; Ho, Nancy MD; Wu Datta, Lisa MS; Zerbe, Christa S. MD; Marciano, Beatriz E. MD; Kuhns, Douglas B. PhD; Kader, Howard A. MD; Holland, Steven M. MD; Malech, Harry L. MD; Brant, Steven R. MDNIDDK IBD Genetics Consortium,

doi: 10.1097/MIB.0000000000000966
Original Article

Background: Approximately, one-third to one-half of children with chronic granulomatous disease (CGD) develop gastrointestinal inflammation characteristic of idiopathic inflammatory bowel disease (IBD), usually Crohn's disease. We hypothesized that the overall IBD genetic risk, determined by IBD genetic risk score (GRS), might in part determine IBD development in CGD.

Methods: We reviewed medical records to establish IBD diagnoses in CGD subjects seen at NIAID. IBD risk single nucleotide polymorphism genotypes were determined using the Immunochip, and GRS were estimated by Mangrove.

Results: Among 157 white patients with CGD, 55 were confirmed, 78 excluded, and 24 were uncertain for IBD. Two hundred one established, independent European IBD risk single nucleotide polymorphisms passed quality control. After sample quality control and removing non-IBD CGD patients with perianal disease, mean GRS for 40 unrelated patients with CGD-IBD was higher than 53 CGD non-IBD patients (in log2-scale 0.08 ± 1.62 versus −0.67 ± 1.64, P = 0.026) but lower than 239 IBD Genetics Consortium (IBDGC) young-onset Crohn's disease cases (0.76 ± 1.60, P = 0.025). GRS for non-IBD CGD was similar to 609 IBDGC controls (−0.69 ± 1.60, P = 0.95). Seven established IBD single nucleotide polymorphisms were nominally significant among CGD-IBD versus CGD non-IBD, including those near LACC1 (P = 0.005), CXCL14 (P = 0.007), and TNFSF15 (P = 0.016).

Conclusions: The weight of the common IBD risk alleles are significant determinants of IBD in CGD. However, IBD risk gene burden among CGD children with IBD is significantly lower than that in nonsyndromic pediatric Crohn's disease, congruent with the concept that defective superoxide production in CGD is also a major IBD risk factor. Individual IBD genes might interact with the CGD defect to cause IBD in CGD.

Supplemental Digital Content is Available in the Text.

*Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland;

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland;

Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland;

§Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland;

Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland; and

**Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.

Address correspondence to: Steven R. Brant, MD, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, 1501 E. Jefferson Street, B136, Baltimore, MD 21231 (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Supported by the Intramural Research Program of NIAID, NIH, Intramural project numbers Z01-A1-00644 and Z01-A1-00988 (S.S.D.R. and H.L.M.), NIH Grant DK062431 (S.R.B.) and the Robert E. Sadler, Jr Family (S.R.B.).

The authors have no conflict of interest to disclose.

C. Huang and S. S. De Ravin share co-first authorship; H. L. Malech and S. R. Brant share co-senior authorship.

Received September 01, 2016

Accepted September 14, 2016

© Crohn's & Colitis Foundation of America, Inc.
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