The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

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.

Diabetes and cancer risk: A Mendelian randomization study

“…Our results are in general agreement with those reported in earlier MR studies with case–control data mainly conducted among European populations using a case–control strategy . A recent MR study led by researchers from the International Agency for Research on Cancer investigated the associations of type 2 diabetes and metabolic factors with pancreatic cancer among 7,110 pancreatic cancer patients and 7,264 controls .…”

“…Our results are in general agreement with those reported in earlier MR studies with case-control data mainly conducted among European populations using a case-control strategy. 7,8 A recent MR study led by researchers from the International Agency for Research on Cancer investigated the associations of type 2 diabetes and metabolic factors with pancreatic cancer among 7,110 pancreatic cancer patients and 7,264 controls. 7 Using 43 of the susceptibility SNPs for type 2 diabetes, their MR analysis indicated that diabetes was not significantly associated with pancreatic cancer (odds ratio = 1.03; 95% CI = 0.85-1.11; p = 0.47).…”

“…Large‐scale MR studies have been increasingly reported in recent years . However, these studies often consist of mixed populations mainly from traditional case–control studies, with high risk of selection bias and heterogeneity, and lack important information about lifestyle factors prior to the onset of cancer.…”

“…6 Large-scale MR studies have been increasingly reported in recent years. 7,8 However, these studies often consist of mixed populations mainly from traditional case-control studies, with high risk of selection bias and heterogeneity, and lack important information about lifestyle factors prior to the onset of cancer. Thus, MR studies from prospective cohort studies with detailed covariates at baseline would probably give less biased estimates than those from case-control studies.…”

Hospital‐diagnosed overweight and obesity related to cancer risk: a 40‐year Danish cohort study

“…Diabetes and alcoholism‐related comorbidities had strong impacts on that association. Diabetes might contribute to the increased pancreatic cancer risk associated with overweight and obesity, observed here and elsewhere . Additionally, consistent with previous research , patients diagnosed with overweight and obesity that had a history of alcoholism‐related diseases also had an elevated risk of cancer, particularly gastric cancer .…”