Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements
Karl Smith-Byrne, Agustin Cerani, Florence Guida, Sirui Zhou, Antonio Agudo, Krasimira Aleksandrova, Aurelio Barricarte, Miguel Rodríguez‐Barranco, Christoph H. Bochers, Inger Torhild Gram, Jun Han, Christopher I. Amos, Rayjean J. Hung, Kjell Grankvist, Therese Haugdhal Nøst, Liher Imaz, María‐Dolores Chirlaque, Mikael Johansson, Rudolf Kaaks, Tilman Kühn, Richard M. Martin, James McKay, Valeria Pala, Hilary A. Robbins, Torkjel M. Sandanger, David Schibli, Matthias B. Schulze, Ruth C. Travis, Paolo Vineis, Elisabete Weiderpass, Paul Brennan, Mattias Johansson, J. Brent Richards
Abstract
BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. 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 = 7,824) and lung cancer risk (n = 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 = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 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.