Circulating isovalerylcarnitine and lung cancer risk: evidence from mendelian randomization and pre-diagnostic blood measurements

Karl Smith-Byrne, Agustin Cerani, Florence Guida, Sirui Zhou, Antonio Agudo, Krasimira Aleksandrova, Aurelio Barricarte, Miguel Rodríguez-Barranco, Christoph H Borchers, Inger T Gram, Christopher I Amos, Rayjean J Hung, Kjell Grankvist, Therese H Nøst, Liher Imaz, María Dolores Chirlaque-López, Mikael Johansson, Rudolf Kaaks, Richard M Martin, Tilman KühnJames D 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

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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 1,309 matched controls) was subsequently performed using pre-diagnostic 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 pre-diagnostic blood found similar results (Log10-OR = 0.39, 95% CI: 0.21-0.72). Results were consistent across lung cancer sub-types.

CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodological 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 aetiology. 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.

Original languageEnglish
Pages (from-to)1966–1974
JournalCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume31
Issue number10
Early online date15 Jul 2022
DOIs
Publication statusPublished - 01 Oct 2022
Externally publishedYes

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