Interaction Between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk

Authors

• Meredith S. Duncan, University of KentuckyFollow
• Hector Diaz-Zabala, Vanderbilt University
• James Jaworski, Vanderbilt University
• Hilary A. Tindle, VA Medical Center
• Robert A. Greevy, Vanderbilt University
• Loren Lipworth, Vanderbilt University
• Rayjean J. Hung, Samuel Lunenfeld Research Institute
• Matthew S. Freiberg, Vanderbilt University
• Melinda C. Aldrich, Vanderbilt University

Abstract

Background: Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime packyears smoked. Methods: We analyzed data from participants of European ancestry in the Framingham Heart StudyOriginal (n = 454) andOffspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics froma recent study in theOncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education. Results: We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR=1.48 at mean PRS, and HR=1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years). Conclusions: These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk. Impact: These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk.

Document Type

Article

Publication Date

4-1-2024

Notes/Citation Information

Publisher Copyright: © 2024 The Authors; Published by the American Association for Cancer Research.

Digital Object Identifier (DOI)

10.1158/1055-9965.EPI-23-0571

Archival?

Archival

Repository Citation

Duncan, Meredith S.; Diaz-Zabala, Hector; Jaworski, James; Tindle, Hilary A.; Greevy, Robert A.; Lipworth, Loren; Hung, Rayjean J.; Freiberg, Matthew S.; and Aldrich, Melinda C., "Interaction Between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk" (2024). Biostatistics Faculty Publications. 168.
https://uknowledge.uky.edu/biostatistics_facpub/168