Evaluating the Impact of Oral Contraceptives on Pancreatic Cancer Risk: A Two-Sample Mendelian Randomization Analysis

Area of Science:

• Genetics
• Oncology
• Pharmacology

Background:

• The link between oral contraceptive (OC) use and pancreatic cancer (PC) risk is debated due to inconsistent observational study findings.
• Unbiased and robust methods are needed to clarify the association and identify PC prevention strategies.

Purpose of the Study:

• To investigate the potential causal relationship between oral contraceptive use and pancreatic cancer risk.
• To identify specific drug-targeted proteins that may mediate this association.

Main Methods:

• Two-sample Mendelian randomization (MR) analysis using blood protein quantitative trait loci (pQTLs) as instrumental variables.
• Sensitivity analyses, colocalization, reverse MR, pathway enrichment, and protein-protein interaction network analysis were conducted.
• Investigated causal effects of protein-coding genes on PC risk and their single-cell expression patterns.

Main Results:

• MR analysis identified five drug-targeted proteins significantly associated with PC risk.
• Elevated COMT, AGT, FN1, UGT1A1 and reduced SERPINC1 levels were linked to increased PC risk.
• AGT, FN1, and COMT showed consistent associations across analyses, supporting their role in PC risk.

Conclusions:

• Genetic evidence suggests a potential causal link between oral contraceptive use and increased pancreatic cancer risk in European groups.
• This association may be mediated by drug-targeted proteins, including AGT and FN1.
• Further research is crucial to understand the mechanisms and implications of OC use on PC risk.