Genetic risk factors for serious infections in inflammatory bowel diseases

Abstract

Introduction: Immunosuppression, the cornerstone of management of Crohn’s disease (CD) and ulcerative colitis (UC) (inflammatory bowel diseases; IBD) is associated with an increased risk of serious infections that is inadequately predicted by clinical risk factors. The role of genetics in determining susceptibility to infections is unknown.

Methods: From a prospective-consented patient registry, we identified IBD patients with serious infections requiring hospitalization. Analysis was performed to identify IBD-related and non-IBD related immune response loci on the Immunochip that were associated with serious infections and a genetic risk score (GRS) representing the cumulative burden of the identified single nucleotide polymorphisms was calculated. Multivariable logistic regression used to identify effect of clinical and genetic factors.

Results: The study included 1333 IBD patients (795 CD, 538 UC) with median disease duration of 13 years. A total of 133 patients (10%) had a serious infection requiring hospitalization. Patients with infections were more likely to have CD and had shorter disease duration. The most common infections were skin and soft-tissue, respiratory and urinary tract infections. Eight IBD risk loci and two other polymorphisms were significantly associations with serious infections. Each one point increase in the infection GRS was associated with a 50% increase in risk of infections (OR = 1.53, 95% CI = 1.37–1.70) (p = 1 × 10⁻¹⁴), confirmed on multivariable analysis. Genetic risk factors improved performance of a model predicting infections over clinical covariates alone (p < 0.001).

Conclusions: Genetic risk factors may predict susceptibility to infections in patients with IBD.

Keywords:

• Genetics
• infections
• pneumonia
• immunosuppression
• Crohn’s disease
• sepsis

Acknowledgements

S.S.: study design, analysis and interpretation of data, drafting of article, critical revision of the article for important intellectual content. V.Y., H.K., J.G. and R.X.: data collection, drafting of the article, critical revision of the article for important intellectual content. A.N.A.: study design, data collection, analysis and interpretation of data, drafting of the article, critical revision of the article for important intellectual content.

Disclosure statement

S.S., V.Y., J.G. and R.X. report no conflicts of interest. H.K. received consulting fees from Abbvie, Inc. A.N.A. has served on the Scientific Advisory Boards for Merck, Takeda, Abbvie and Exact Sciences, and has received grant support from Merck and Amgen. The authors alone are responsible for the content and writing of this article.

A.N.A. is supported in part by a grant from the National Institutes of Health (K23 DK097142). This work is also supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A.N.A. has served on the scientific advisory boards for Abbvie, Takeda, Exact Sciences, and Merck and has received grant support from Merck and Amgen.

Additional information

Funding

A.N.A. is supported in part by a grant from the National Institutes of Health (K23 DK097142). This work is also supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A.N.A. has served on the scientific advisory boards for Abbvie, Takeda, Exact Sciences, and Merck and has received grant support from Merck and Amgen.