Assessing the protective role of allergic disease in gastrointestinal tract cancers using Mendelian randomization analysis
Authors: Shuai Yuan, Mathew Vithayathil, Siddhartha Kar, Paul Carter, Amy M. Mason, Shao‐Hua Xie, Stephen Burgess, Susanna C. Larsson
Journal: Allergy (2020)

To the Editor, Immune hypersensitivity featured among allergic individuals has been proposed to enhance immune surveillance, thereby inhibiting abnormal cell growth and thus reduce cancer risk.1, 2 Similarly, the prophylaxis theory suggests that allergy symptoms may prevent cancer development by removing potential carcinogens.2 This hypothesis envisages a preventive role specifically for cancers of tissues that interface with the external environment, such as gastrointestinal tract cancers.2 A reduced risk of gastrointestinal tract cancer among individuals with self-reported allergic conditions has been observed in several but not all observational studies.3, 4 However, whether the associations are causal remains unclear as observational studies are prone to residual confounding. Therefore, we conducted a Mendelian randomization study5 to determine the causal role of genetic liability to allergic disease in esophageal, gastric, and colorectal cancers. One hundred and thirty-six single-nucleotide polymorphisms (SNPs) associated with at least one allergic disease (asthma, allergic rhinitis, or eczema) at P < 3×10−8 in 180 129 cases and 180 709 non-cases of European ancestry were considered as instrumental variables.6 The 136 SNPs were independent and not in linkage disequilibrium defined by distance >1 Mb and r2 < 0.02. The SNPs explained around 2.6% of phenotypic variance. Summary-level data for the associations of those SNPs with esophageal, gastric, and colorectal cancers were obtained from the UK Biobank, BioBank Japan, and FinnGen consortium. The main analysis was based on the multiplicative random-effects inverse-variance weighted method, and estimates from the different studies were combined using fixed effects meta-analysis. The inverse-variance weighted method under a fixed effects model and the weighted median, MR-Egger regression, and MR-PRESSO methods were employed as sensitivity analyses. The I2 (%) statistic and Cochrane's Q value were calculated to assess heterogeneity among estimates of individual SNPs. We considered associations with P values below .017 (where P = .05/3) to represent strong evidence of causal associations and associations with P values below .05 but above .017 as suggestive evidence of associations. Genetic liability to allergic disease was associated with lower risk of the gastrointestinal tract cancers in the meta-analysis of UK Biobank, BioBank Japan, and FinnGen, though the association with gastric cancer was not statistically significant after correcting for multiple testing (Figure 1). The combined odds ratio was 0.85 (95% confidence interval, 0.75, 0.97; P = .016) for esophageal cancer, 0.90 (95% confidence interval, 0.82, 0.98; P = .020) for gastric cancer, and 0.91 (95% confidence interval, 0.86, 0.96; P = .001) for colorectal cancer for one unit increase in log-transformed odds of allergic disease. The associations were consistent across data sources with the exception of the estimate for gastric cancer in FinnGen which was above one but with a broad confidence interval that overlapped the estimates in UK Biobank and BioBank Japan. Results were consistent in sensitivity analyses for all three cancer outcomes (Table 1). A potential limitation arises from the fact that we used an instrument for liability to allergic disease that was developed using genetic data from individuals of European ancestry and applied to a Japanese population. However, a consistent effect of risk alleles of SNPs for allergic disease on asthma in BioBank Japan indicates a high validity of used instrumental variables and a negligible population bias. In addition, a robust pattern of established associations in both Asian and European populations suggested that the associations were portable across populations of distinct ancestries. A further limitation of this work is that we cannot make specific inferences about the impact of food allergies on cancer risk. In summary, this MR study supports a protective effect of allergic disease against esophageal and colorectal cancer and possibly gastric cancer. This finding may be useful for further laboratory studies to understand the immunological pathways involved in gastrointestinal tract carcinogenesis. Genetic instruments for allergic disease were obtained from a published meta-analysis of genome-wide association studies.6 Genetic association estimates for esophageal, gastric, and colorectal cancers were obtained from the UK Biobank study, BioBank Japan, and FinnGen consortium. The authors thank all investigators for sharing these data. Analyses of UK Biobank data were performed under application 29202. Dr. Mason reports grants from the EC-Innovative Medicines Initiative (BigData@Heart) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). All studies included in cited genome-wide association studies had approved by a relevant review board. The present MR analyses were approved by the Swedish Ethical Review Authority (2019-02793). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.