The ratio of omega-6 fatty acids to omega-3 fatty acids mediating the effect of gastroesophageal reflux disease on pancreatic cancer risk: a two-step mediation Mendelian randomisation study.

[INTRODUCTION] Pancreatic cancer (PC) is the third most common cause of cancer-related deaths worldwide, with the 5-year survival rate for patients with PC in developed countries being only 9-10%. Gastroesophageal reflux disease (GERD) is known to be a high-risk factor for several cancers. However, the relationship between GERD and PC remains controversial. Therefore, this study aimed to investigate the causal association between GERD and the risk of PC. Additionally, we sought to validate the role of omega-6/omega-3 polyunsaturated fatty acids (n-6/n-3 PUFA) as mediators in this pathway by calculating their mediating effect.

[METHODS] First, a two-step, two-sample Mendelian randomisation (TSMR) framework was established to test the causal relationship between GERD and PC and to determine whether n-6/n-3 PUFA could act as a mediator of the causal pathway. Subsequently, using multivariate Mendelian randomisation (MVMR), the proportion of mediators mediated by n-6/n-3 PUFA was calculated using the product of coefficients approach.

[RESULTS] The two-step TSMR results showed that GERD was positively associated with PC (n = 27 SNPs, OR 2.07 95% CI 1.27-3.39, P = 0.003 β = 0.72). Additionally, GERD was positively associated with n-6/n-3 PUFAs (n = 59 SNPs, OR 1.06, 95% CI 1.02-1.11 P = 0.001, β1 = 0.06), which are positively associated with PC (n = 28 SNPs, OR 1.23, 95% CI 1.04-1.46, P = 0.02, β = 0.20). The MRMV results demonstrated that after controlling for GERD, the n-6/n-3 PUFA had an impact on PC (n = 17 SNPs, se = 0.07, P = 0.004, β2 = 0.21). Furthermore, the causal effect of GERD on PC was partially mediated through the n-6/n-3 PUFA (n = 31 SNPs, se = 0.20, P = 0.03, β3 = 0.42) with a 2.9% mediating effect.

[CONCLUSION] This study provides insights into the pathological processes that link GERD to PC. In addition, it offers a novel approach to PC prevention and early detection. In clinical practice, early screening and drug usage control in patients with GERD must be prioritised. Furthermore, dietary supplementation with n-3 PUFAs and proper n-6 PUFA reduction may minimise the prevalence of PC.