Abstract
BACKGROUND: The role of immune cells in cancer pathogenesis remains controversial due to conflicting reports, potentially arising from various confounding factors. Emerging evidence suggests that cancer can also influence immune cell populations and functions, making it challenging to investigate their causal relationship. Traditional observational studies often fail to eliminate all confounding factors and are prone to reverse causality. Therefore, we employ Mendelian randomization (MR) to determine the causal relationship between immune cells and cancer, as this method can identify causal relationships independent of confounding factors and avoid reverse causality. METHODS: Genome-wide association study (GWAS) summary statistics on immune traits, encompassing 310 immune cell phenotypes, were obtained from 3,757 European individuals, with peripheral blood immune cells tested using flow cytometry. GWAS summary statistics for gastric cancer were derived from 476,116 European individuals across two large-scale biobanks: the UK Biobank and FinnGen. Gastric cancer was identified by the International Classification of Diseases, 9th Revision (ICD-9), and 10th Revision (ICD-10) codes. Significant single nucleotide polymorphisms (SNPs) for immune traits were extracted at a threshold of P<1×10(-5), while a threshold of P<5×10(-8) was used for gastric cancer GWAS data. Linkage imbalance-based clumping was performed to obtain independent SNPs, and those with F<10 were excluded to mitigate weak instrument bias. Phenoscanner V2 was used to exclude SNPs directly associated with potential confounders or outcomes. Two-sample MR was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. A false discovery rate (FDR) correction was used to reduce the likelihood of type 1 errors. In addition, we conducted MR-Egger intercept tests and Cochran's Q tests. RESULTS: The numbers of CD4(-)CD8(-) T cells and IgD(-)CD27(-) B cells were positively correlated with the development of gastric cancer, with odds ratios (ORs) of 1.15 [95% confidence interval (CI), 1.07-1.24; P<0.001; P(FDR)=0.041; IVW method] and 1.07 (95% CI, 1.03-1.11; P=0.001; P(FDR)=0.187; IVW method), respectively. However, the percentage of IgD(+)CD24(-) B cells in lymphocytes were negatively associated with the development of gastric cancer (OR =0.90; 95% CI, 0.84-0.96; P=0.002; P(FDR)=0.187; IVW method). MR analysis of the above three immune cell phenotypes showed no significant heterogeneity or horizontal pleiotropy. In the reverse MR analysis, gastric cancer was not causally associated with any of the immune cell phenotypes. CONCLUSIONS: Circulating CD4(-)CD8(-) T cells and IgD(-)CD27(-) B cells are positively correlated with the development of gastric cancer, while the percentage of IgD(+)CD24(-) B cells in lymphocytes are negatively correlated. These findings provide insight into the relationship between immune cells and gastric cancer pathogenesis and may serve as a basis for the development of immunotherapies for gastric cancer.