Pumping Iron: Exploring Novel Gene-environment Interactions in the Inflammatory Bowel Diseases

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The inflammatory bowel diseases (IBD) are believed to be environmentally driven diseases occurring in genetically susceptible individuals.1 With the advent of genome-wide association studies, over 200 susceptibility loci for IBD have been identified.2 Gene mutation studies suggest that the pathogenesis of Crohn's disease and ulcerative colitis results from an abnormal interaction between the gut's immune system and the intestinal microbiome.3 Epidemiologic studies have shown that the incidence of IBD in the Western world rose rapidly throughout the 20th century.4 In contrast, IBD was relatively rare in developing countries in the 20th century.4 However, at the start of the 21st century, newly industrialized countries in Asia, the Middle East, and South America have documented a rising incidence of IBD.5 These epidemiologic patterns imply that IBD emerges—and its incidence accelerates—as societies become similar to Western countries in such things like diet, sanitization, agriculture, manufacturing, pollution, transportation, and urbanization.6 Numerous studies have explored environmental risk factors of IBD associated with Westernization,7,8 unfortunately, few environmental determinates have been consistently demonstrated to modulate the occurrence of Crohn's disease and ulcerative colitis.9
One enticing area of exploration has been studying dietary changes in modern Western societies.10 As societies become wealthier, the ratio of calories arising from plants versus meats shifts toward meat (e.g., beef, pork, and lamb).5,11 In this issue, Khalili et al12 hypothesized that the rising consumption of dietary iron and heme iron may increase the risk of developing Crohn's disease and ulcerative colitis. The authors used the Nurses' Health Study to capture dietary habits in the cohort before diagnosis of IBD. The authors did not find an association between dietary total iron or heme iron and the risk of developing Crohn's disease or ulcerative colitis.12 In the past, this null association would have been interpreted as a negative study with methodological caveats: for example, the lack of power to detect an association with only 261 Crohn's disease and 321 ulcerative colitis cases, exposure misclassification of dietary iron or heme iron from the food frequency questionnaire, and generalizability as the study population is restricted to women diagnosed in a certain age group.13,14 However, another important limitation of detecting novel environmental risk factors in past case-control and cohort studies of IBD has been the omission of evaluating environmental determinates in the context of genetic susceptibility, if only because of lack of knowledge (pregene studies) or lack of capacity (no available genetic material).9
The second phase of Khalili et al12 study was to evaluate for gene–environment interactions that modify the association between total iron and heme iron and the development of Crohn's disease and ulcerative colitis. The authors evaluated a sub-sample of cases and controls with biobanked DNA for genotyping of the single nucleotide polymorphisms identified in meta-analysis of genome-wide association studies.3 After accounting for potential environmental confounders and correcting for multiple comparison error, the authors demonstrated that among women who carried the AA genotype of FcγRIIA gene, the odds of ulcerative colitis increased by 2.76 (95% CI: 1.02–7.48) for every 1 g increase in dietary heme iron intake.10 In contrast, women with the GG genotype FcγRIIA were less likely to develop ulcerative colitis with each 1 g increase in dietary heme iron. A gene–environment interaction was not observed for Crohn's disease and either total iron or heme iron consumption, or for ulcerative colitis and total iron consumption. In the discussion of the paper, the authors comprehensively explain the function of the FcγRIIA gene and theorize potential mechanisms for the paradoxical effect of dietary heme iron consumption among women carrying different single nucleotide polymorphisms.

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