Genetic evidence for a causal relationship between innate leukocytes and risk of digestive system cancers in East Asians and Europeans

Abstract

AbstractBackground Immune dysregulation plays an important role in cancer onset and development. The causal relationships between innate leukocytes prior to cancer and the risk of digestive system cancers remain unknown. This study assesses the causal correlations between white blood cells (WBC) and digestive system cancer risk in East Asians and Europeans. Methods Summary-level data of WBC-related genetic variation were extracted from Biobank Japan (107,964 and 62,076 participants), and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analysis was performed in East Asians and Europeans separately. Results Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in the East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69–0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77–0.97, P = 0.013). An inverse suggestive association was observed between levels of basophil and risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72–0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57–0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70–0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67–0.94, P = 0.007). Conclusions Our MR analyses reveal the genetically causal effect of blood eosinophils on decreased risk of CRC in both Europeans and East Asians, and of basophils on decreased risk of GC in Europeans.