RT Journal Article
T1 Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.
A1 Smith-Byrne, Karl
A1 Cerani, Agustin
A1 Guida, Florence
A1 Zhou, Sirui
A1 Agudo, Antonio
A1 Aleksandrova, Krasimira
A1 Barricarte, Aurelio
A1 Barranco, Miguel Rodríguez
A1 Bochers, Christoph H
A1 Gram, Inger Torhild
A1 Han, Jun
A1 Amos, Christopher I
A1 Hung, Rayjean J
A1 Grankvist, Kjell
A1 Nøst, Therese Haugdhal
A1 Imaz, Liher
A1 Chirlaque-López, María Dolores
A1 Johansson, Mikael
A1 Kaaks, Rudolf
A1 Kühn, Tilman
A1 Martin, Richard M
A1 McKay, James D
A1 Pala, Valeria
A1 Robbins, Hilary A
A1 Sandanger, Torkjel M
A1 Schibli, David
A1 Schulze, Matthias B
A1 Travis, Ruth C
A1 Vineis, Paolo
A1 Weiderpass, Elisabete
A1 Brennan, Paul
A1 Johansson, Mattias
A1 Richards, J Brent
K1 Case-Control Studies
K1 Humans
K1 Polymorphism, Single Nucleotide
AB 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. 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). 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. 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. 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.
PB American Association for Cancer Research
YR 2022
FD 2022-07-13
LK http://hdl.handle.net/10668/20182
UL http://hdl.handle.net/10668/20182
LA en
NO Smith-Byrne K, Cerani A, Guida F, Zhou S, Agudo A, Aleksandrova K, et al. Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements. Cancer Epidemiol Biomarkers Prev. 2022 Oct 4;31(10):1966-1974.
NO Mattias Johansson and Karl Smith-Byrne were supported by grants from the US National Cancer Institute under award number U19CA203654 and Cancer Research UK (C18281/A29019). This work was also supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de Recherche Santé Québec (FRSQ), and the FRQS Clinical Research Scholarship. Metabolite GWAS studies were conducted within TwinsUK, which is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas's NHS Foundation Trust in partnership with King's College London. The INTEGRAL-ILCCO OncoArray data collection was supported by National Institute of Health under award number U19CA203654.We thank our collaborators from the International Lung Cancer Consortium (ILCCO) Adonina Tardon, Angela Risch, Angeline Andrew, Chu Chen, David Christiani, Demetrios Albanes, Erich Wichmann, Gadi Rennert, Geoffrey Liu, Hans Brunnström, Heike Bickeböller, Hongbing Shen, Jian-Min Yuan, John K. Field, John R. McLaughlin, Kjell Grankvist, Lambertus A. Kiemeney, Loic Le Marchand, M. Dawn Teare, Maria Teresa Landi, Matthew B. Schabath, Melinda C. Aldrich, Mikael Johansson, Neil Caporaso, Olle Melander, Philip Lazarus, Richard Houlston, Sanjay S. Shete, Shan Zienolddiny, Stephen Lam, Stig E. Bojesen, Susanne Arnold, Thorunn Rafnar, Victoria Stevens, Ying Wang, and Yun-Chul Hong.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
DS RISalud
RD Apr 4, 2025