Genetic Risk for Inflammatory Bowel Disease Is a Determinant of Crohnʼs Disease Development in Chronic Granulomatous Disease

Abstract

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 (CD). We hypothesized that overall IBD genetic risk, determined by IBD genetics 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 SNP genotypes were determined using the Immunochip and GRS were estimated by Mangrove. Results Among 157 Caucasian CGD patients 55 were confirmed, 78 excluded and 24 were uncertain for IBD. 201 established, independent European IBD risk SNPs passed quality control. After sample quality control and removing non-IBD CGD patients with perianal disease, mean GRS for 40 unrelated CGD-IBD patients was higher than 53 CGD non-IBD patients (in log2-scale 0.08±1.62 vs. −0.67±1.64, p=0.026) but lower than 239 IBD Genetics Consortium (IBDGC) young-onset CD 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 SNPs were nominally significant among CGD-IBD vs. CGD non-IBD, including those near LACC1 (p=0.005), CXCL14 (p=0.007) and TNFSF15 (p=0.016). Conclusions The weight of 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 non-syndromic pediatric CD, 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.

Mucosal Microbiome Profiles Polygenic Irritable Bowel Syndrome in Mestizo Individuals

“…The rs254560_AG SNP in the C5orf66 gene on chromosome 5 found in this study is similar to genes such as CCND280, GLI381, or RB1CC182, which have been described as regulatory CNS proteins that modify transcriptional activity and contribute to brain growth trajectory changes at different biological levels, ranging from cellular changes, brain organization differences and complex phenotypic traits (Kuhlwilm and Boeckx, 2019). The weights of common IBD risk alleles are significant determinants during chronic granulomatosis diseases (CGD) (Huang et al, 2016). Based on general linear models, gray matter (GM) alterations caused by SNPs and Early Adverse Life events (EALs) are predictive of IBS.…”

Inflammatory bowel disease in chronic granulomatous disease: An emerging problem over a twenty years' experience

“…Recent findings demonstrate the role of NADPH oxidase complex in regulating gut immunity, regardless of susceptibility to infections . Furthermore, additional genetic factors are determinant in CGD‐IBD development, such as common IBD risk alleles …”

“…7 Furthermore, additional genetic factors are determinant in CGD-IBD development, such as common IBD risk alleles. 8 Despite new insights into the pathophysiology and clinical characterization of CGD-IBD, the management of the disease is still based on experience with polygenic conventional IBD. Nonetheless, specific features of CGD-IBD must be considered, namely the increased risk of immunosuppressant agents, the risks of anesthesia/sedation for endoscopy procedures in patients with respiratory impairment, and the option of "definitive" therapeutic intervention with hematopoietic stem cell transplantation (HSCT).…”

New onset colitis in an adult patient with chronic granulomatous disease treated with hematopoietic stem cell transplantation: a diagnostic dilemma

“…The presence of mucosal bridges is a known phenomenon seen in Crohn’s disease [ 21 – 24 ], but pathology only reported nonspecific granulomatous inflammation, not in keeping with the classic histologic findings of Crohn’s disease. Although the risk of IBD is elevated in patients with CGD [ 25 , 26 ], our gastroenterologist colleagues felt that the absence of autoimmune disease in both the patient’s and donor’s past medical history was not in keeping with an autoimmune inflammatory bowel disease. Verification with the donor registry has confirmed that the donor has not experienced any gastrointestinal complications to date.…”