Abstract

BackgroundRisk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.MethodsWe identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses.ResultsResults indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias.ConclusionsOur results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

Highlights

  • Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes

  • We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology

  • The genetic instrument for body mass index (BMI) comprising 95 instrumental SNPs indicated that the effect of each SD increase in BMI (4.6 kg/ m2) increased pancreatic cancer risk (Figure 1)

Read more

Summary

Introduction

Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call