Antihypertensive drug targets and pancreatitis reporting signals: An integrative mendelian randomization and FAERS pharmacovigilance study
Chang-Lei Li, Si-Han Wang, Zhi-Yuan Yao, Xiao-Tong Cui, Zu-Sen WangObjective
To investigate whether genetically proxied antihypertensive drug targets are associated with pancreatic exocrine diseases and whether corresponding antihypertensive agents show pancreatitis-related pharmacovigilance signals.
Methods
This integrative genetic epidemiology and pharmacovigilance study combined linkage disequilibrium score regression, two-sample Mendelian randomization, summary-data-based Mendelian randomization, Bayesian colocalization, and FAERS disproportionality analysis. Publicly available GWAS summary statistics were derived predominantly from European-ancestry participants, and whole-blood cis-eQTLs were used to genetically proxy antihypertensive drug-target expression. FAERS reports submitted from 2004 to 2023 were analyzed for pancreatitis-related reporting signals.
Results
Among 21 antihypertensive drug targets, ADRB2, CACNA1I, JUN, NR3C2, and SLC12A4 showed nominal associations with pancreatic outcomes; however, none remained significant after Bonferroni correction. Absolute PP.H4 values did not support robust colocalization. Although several target-outcome pairs had high conditional PP.H4 values, these findings provide only relative support for H4 over H3 when both traits are assumed to have regional association signals. Several antihypertensive agents also generated pancreatitis-related reporting signals in FAERS; these signals do not quantify incidence or establish causality.
Conclusions
The findings are exploratory and prioritize selected antihypertensive targets and drugs for replication and mechanistic study. They do not establish causal effects, robust colocalization, or an increased incidence of pancreatitis.