ARE PEOPLE WITH FAMILY HISTORY OF PANCREATIC CANCER ENRICHED WITH GENETIC PROPENSITY FOR DIABETES MELLITUS?
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Background
Observational studies suggest that long-standing diabetes may be a cause of pancreatic cancer. To further support this observation, we aimed to determine whether the genetic risk of diabetes is associated with a family history of pancreatic cancer in persons without a personal history of pancreatic cancer. We hypothesized that if diabetes is a cause of pancreatic cancer, then persons with a family history of pancreatic cancer, reflecting both inheritance and lifestyle risk factors, will be enriched with a genetic propensity for diabetes. Our hypothesis assumes that the causal genes for diabetes and pancreatic cancer are not identical.
Methods
We conducted a cross-sectional analysis of 3,911 participants without a personal history of pancreatic cancer using data from the All of Us Research Program. Family history of pancreatic cancer was assessed through structured electronic health record reviews and self-reported questionnaires capturing first- and second-degree relatives’ cancer histories. A polygenic score (PGS) for type II diabetes was created using short-read whole genome sequencing (srWGS) data in All of Us . Logistic regression was used to test the association between family history (first degree relative) of pancreatic cancer and polygenic risk for diabetes, adjusting for relevant demographic and lifestyle variables.
Results
Mean age was 65.7 years, with 64.8% women and 83.4% White participants. Among the 3,911 participants,173 individuals (4.4%) had a family history of pancreatic cancer. Diabetes PGS was not associated with a higher OR of a family history of pancreatic cancer; OR for higher PGS was 0.67 (95% CI 0.45-0.98) before adjustment and 0.67 (95% CI 0.44-0.97) after adjustment. Restricting to participants ≤50 years among whom we expected a lower likelihood of survival bias, the association was attenuated (OR= 0.75, 95% CI 0.47- 1.18). In contrast, the OR was even more inverse in participants >50 years (OR= 0.60, 95% CI 0.38-0.94). Simulations further support the potential for survival bias.
Conclusions
Contrary to the hypothesis, persons with a family history of pancreatic cancer were not enriched with genetic risk of diabetes. The observed inverse association may be partially due to survival bias. This work points to complexities in the conduct of etiologic research using a cross-sectional design.
