Familial risk of pancreatic cancer and interaction with hyperglycemia, smoking, and obesity among first-degree relatives.

BACKGROUND: The influence of hyperglycemia, smoking, and obesity on the familial risk of pancreatic cancer (PC) is incompletely understood. We quantified the risk of PC in first-degree relatives (FDRs) and evaluated potential interactions between family history and these modifiable factors. METHODS: Using the Korean National Health Insurance Database, we identified 6,217,057 individuals from 1.7 million families containing at least one FDR and followed them from 2002 to 2018. Hazard ratios (HRs) for incident PC were estimated for individuals with versus without an affected FDR. Additive interaction between family history and hyperglycemia, smoking, or obesity was assessed with the relative excess risk due to interaction (RERI). RESULTS: Individuals with an affected FDR had 43 newly diagnosed cases of PC, with an adjusted HR of 2.46 (95% CI, 1.81–3.33), corresponding to an incidence of 0.51 per 10,000 person-years. Risk was greatest when the affected relative was a sibling (HR 13.57; 95% CI, 6.08–30.26), followed by an affected mother (HR 2.35; 95% CI, 1.45–3.78) and father (HR 2.05; 95% CI, 1.32–3.19). Familial risk was higher in younger participants and in women. Among those with an affected FDR, hyperglycemia (HR 3.48; 95% CI, 1.12–10.82), smoking (HR 3.24; 95% CI, 2.13–4.93), and obesity (HR 2.89; 95% CI, 1.81–4.62) further increased PC risk. RERI values were close to zero, indicating little additive interaction between family history and these factors. CONCLUSION: FDRs of patients with PC have an approximately 2.5-fold elevated risk, which is further compounded—but not synergistically amplified—by hyperglycemia, smoking, or obesity. Individuals who harbor both familial and lifestyle risk factors should be considered for genetic counseling and life style modification.