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Dietary Iron and Heme Iron Consumption, Genetic Susceptibility, and Risk of Crohn's Disease and Ulcerative Colitis

Khalili, Hamed MD, MPH*,†; de Silva, Punyanganie S. MD, MPH; Ananthakrishnan, Ashwin N. MD, MPH*,†; Lochhead, Paul MD, PhD; Joshi, Amit PhD*,†; Garber, John J. MD*; Richter, James R. MD*; Sauk, Jenny MD*; Chan, Andrew T. MD, MPH*,†,§,‖

doi: 10.1097/MIB.0000000000001161
Clinical Review Article

Background: Dietary iron and heme, likely through their effect on gut commensal bacteria and colonic barrier function, have been shown to modulate colonic inflammation in animal models of colitis. Nonetheless, the link between dietary total and heme iron and risk of Crohn's disease (CD) and ulcerative colitis (UC) has not been previously explored.

Methods: We conducted a prospective cohort study of 165,331 U.S. women enrolled in the Nurses' Health Study and Nurses' Health Study II. Dietary information was collected using a validated food frequency questionnaire at baseline (1984) and updated every 2 to 4 years. Self-reported CD and UC diagnoses were confirmed through medical records review. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals while adjusting for potential confounders. In a case–control study nested within these cohorts, we evaluated the interaction between single-nucleotide polymorphisms associated with genome-wide susceptibility to CD and UC and dietary total and heme iron intake on risk of CD and UC using logistic regression modeling.

Results: Through 2011, over 3,038,049 person-years of follow-up, we documented 261 incident cases of CD and 321 incident cases of UC. Dietary heme iron was nonsignificantly associated with increased risk of UC (Ptrend = 0.12). This association seemed to be modified by the UC susceptibility locus, rs1801274, a coding variant in the FcγRIIA gene (Pinteraction = 7.00E-05). In contrast, there was no association between dietary heme iron and risk of CD (Ptrend = 0.67). We also did not observe an association between total dietary intake of iron and risk of CD or UC (All Ptrend > 0.35).

Conclusion: In 2 large prospective cohort studies, dietary total and heme iron were not associated with risk of CD or UC. Our suggestive finding that the association between dietary heme iron intake and risk of UC may be modified by a coding variant in FcγRIIA gene warrants additional investigation.

Article first published online 9 June 2017.Supplemental Digital Content is Available in the Text.

*Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;

Clinical and Translation Epidemiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;

Division of Gastroenterology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;

§Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and

The Broad Institute, Cambridge, Massachusetts.

Address correspondence to: Hamed Khalili, MD, MPH, Digestive Healthcare Center–Crohn's and Colitis Center, Massachusetts General Hospital, 165 Cambridge Street, 9th Floor, Boston, MA 02114 (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 R01 CA050385, P01 CA87969, CA49449, CA67262, P30 DK043351, K23 DK099681, K08 DK064256, K24 DK098311, K24 DK91417, K23 DK091742, UM1 CA176726, and UM1 CA186107. A. Chan is supported by a senior investigator grant from the Crohn's and Colitis Foundation of America (CCFA). H. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681).

H. Khalili has received consulting fees from AbbVie and Samsung Bioepis. A. N. Ananthakrishnan is a member of the scientific advisory board for Exact Sciences, AbbVie, and Cubist pharmaceuticals. J. R. Richter is a consultant for Policy Analysis, Inc. A. Chan has served as a consultant for Bayer Healthcare, Pfizer Inc., and Alarez Pharmaceuticals. The remaining authors have no conflict of interest to disclose.

The institutional review board at the Partners Healthcare approved this study.

Received February 05, 2017

Accepted March 07, 2017

© Crohn's & Colitis Foundation
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