Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans

Jia Hao Zhu; Ben Jie Xu; Xiang Yi Pang; Jie Lian; Ke Gu; Sheng Jun Ji; Hai Bo Lu

doi:10.14740/wjon1860

Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans

World J Oncol. 2024 Jun;15(3):482-491. doi: 10.14740/wjon1860. Epub 2024 May 7.

Authors

Jia Hao Zhu^{1

2}, Ben Jie Xu^{1

2}, Xiang Yi Pang^{1

2}, Jie Lian¹, Ke Gu³, Sheng Jun Ji⁴, Hai Bo Lu¹

Affiliations

¹ Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China.
² These authors contributed equally to the study.
³ Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, China.
⁴ Department of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, China.

Abstract

Background: Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans.

Methods: Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 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) analyses were performed on East Asians and Europeans separately.

Results: Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in 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 basophils and the 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 revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.

Keywords: Cancers; Causal inference; Digestive system; Leukocyte; Mendelian randomization.

Grants and funding

This work was supported by the National Natural Science Foundation of China (grant no. 62372141,U20A20376, 82303742), Outstanding Master's and Doctoral Theses of Long Jiang in the New Era (grant no.LJYXL2022-017), Heilongjiang Province Postdoctoral Science Foundation (grant no. LBHZ21189), Harbin Medical University Innovative Science Research Funded Project (grant no. 2022-KYYWF-0289), China Postdoctoral Science Foundation (grant no.2022MD713747).