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