Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements
Permanent lenke
https://hdl.handle.net/10037/27964Dato
2022-10-04Type
Journal articleTidsskriftartikkel
Peer reviewed
Forfatter
Smith-Byrne, Karl; Cerani, Agustin; Guida, Florence; Zhou, Sirui; Agudo, Antonio; Aleksandrova, Krasimira; Barricarte, Aurelio; Barranco, Miguel Rodríguez; Bochers, Christoph H.; Gram, Inger Torhild; Han, Jun; Amos, Christopher I.; Hung, Rayjean J.; Grankvist, Kjell; Nøst, Therese Haugdahl; Imaz, Liher; Chirlaque-López, María Dolores; Johansson, Mikael; Kaaks, Rudolf; Kühn, Tilman; Martin, Richard M.; McKay, James D.; Pala, Valeria; Robbins, Hilary A.; Sandanger, Torkjel M; Schibli, David; Schulze, Matthias B.; Travis, Ruth C.; Vineis, Paolo; Weiderpass, Elisabete; Brennan, Paul; Johansson, Mattias; Richards, J BrentSammendrag
Materials and Methods: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n ¼ 7,824) and lung cancer risk (n ¼ 29,266 cases/56,450 controls). A nested case–control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS).
Results: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR ¼ 0.43; 95% CI, 0.29–0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR ¼ 0.39; 95% CI, 0.21–0.72). Results were consistent across lung cancer subtypes.
Conclusions: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. Impact: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.