Exploring Modifiable Risk Factors: Insights from Mendelian Randomization Analyses of Gastric Cancer in East Asian Populations

Abstract

Background: The incidence of gastric cancer (GC) shows strong geographic variation, with the highest incidence occurring in East Asia. Epidemiological studies have linked lifestyle, diet, and inflammatory factors to the risk of GC. However, their causal relationship is subject to debate due to the potential presence of bias. Addressing these uncertainties is vital for guiding effective preventive strategies. Methods: We used genetic variants as instruments via two-sample univariate and multivariate Mendelian randomization (MR) analyses to examine the relationships between 40 potentially modifiable risk factors and gastric cancer in 6563 patients with gastric cancer and 195745 controls. These population data came from a genome-wide association study of people of Asian ancestry and were obtained from BioBank Japan(BBJ). Results: Our multivariable MR analyses provided suggestive evidence of a potential association between genetically predicted concentrations of serum hemoglobin (OR_SD 0.62 [95% CI 0.41 ~ 0.93]; p=0.02), lactate dehydrogenase (OR_SD 0.62 [95% CI 0.41 ~ 0.93]; p<0.001) and alkaline phosphatase (OR _SD0.80 [95% CI 0.73 ~ 0.88]; p <0.001) and a decreased risk of GC. Furthermore, our study revealed a causal link between type 2 diabetes mellitus (OR_SD 0.83, 95% CI=0.73~0.93, P value=0.002) and GC incidence. Conclusions: This analysis identified several potential modifiable factors for gastric cancer, including hemoglobin, lactate dehydrogenase, alkaline phosphatase and T2DM. These findings should be considered when formulating strategies for the primary prevention of GC, thereby informing evidence-based public health policies.