Causal effects of circulating glutamine on colitis, IBD, and digestive system cancers: a Mendelian randomisation study.

Abstract

Backgrounds: There is growing evidence linking glutamine levels to the risk of gastrointestinal diseases, yet the presence of a causal relationship remains uncertain. In this study, we employed a Mendelian randomization (MR) approach to investigate potential causal associations between glutamine and colitis, inflammatory bowel disease (IBD), and digestive tumors. Methods: Genetic instrumental variables for glutamine exposure were identified from a genome-wide association study (GWAS) involving 114,751 participants. We pooled statistics from GWAS of gastrointestinal diseases in European populations, encompassing colitis (cases=1193, controls=461,740), IBD (cases=31,665, controls=33,977), Crohn's disease (cases=17,897, controls=33,977), ulcerative colitis (cases=1,239, controls=990), oesophageal cancer (cases=740, controls=372,016), gastric cancer (cases=6,563, controls=195,745), liver cell carcinoma (cases=168, controls=372,016), hepatic bile duct cancer (cases=418, controls=159,201), pancreatic cancer (cases=1,196, controls=475,049), and colon cancer (cases=1,494, controls=461,439). To ensure the validity of our findings, we utilized several analytical approaches including inverse variance weighted, weighted median, weighted mode, MR-Egger, and simple mode method. Results: Using the IVW method, we found that glutamine levels were inversely associated with colon cancer (OR = 0.998; 95% CI: 0.997-1.000; P = 0.027), colitis (OR = 0.998; 95% CI: 0.997-1.000; P = 0.020), and IBD (OR = 0.551; 95% CI: 0.343-0.886; P = 0.014). Subgroup analysis revealed a negative association between glutamine and Crohn's disease (OR = 0.375; 95% CI: 0.253-0.557; P = 1.11E-06), but not with ulcerative colitis (OR = 0.508; 95% CI: 0.163-1.586; P = 0.244). Glutamine levels showed no significant correlation with oesophageal cancer (OR = 1.000; 95% CI: 0.999-1.001; P = 0.566), gastric cancer (OR = 0.966; 95% CI: 0.832-1.121; P = 0.648), liver cell carcinoma (OR = 1.000; 95% CI: 0.999-1.000; P = 0.397), hepatic bile duct cancer (OR = 0.819; 95% CI: 0.499-1.344; P = 0.430), and pancreatic cancer (OR = 1.130; 95% CI: 0.897-1.423; P = 0.301). Sensitivity analyses also supports this finding, affirming the reliability and robustness of our study. Conclusions: This study suggests that blood glutamine levels in European populations may lower the risk of colon cancer, colitis, and IBD, particularly Crohn's disease. Nevertheless, additional research involving a diverse range of ancestries is imperative to corroborate this causal relationship.