TY - JOUR
T1 - Circulating isovalerylcarnitine and lung cancer risk: evidence from mendelian randomization and pre-diagnostic blood measurements
AU - Smith-Byrne, Karl
AU - Cerani, Agustin
AU - Guida, Florence
AU - Zhou, Sirui
AU - Agudo, Antonio
AU - Aleksandrova, Krasimira
AU - Barricarte, Aurelio
AU - Rodríguez-Barranco, Miguel
AU - Borchers, Christoph H
AU - Gram, Inger T
AU - Amos, Christopher I
AU - Hung, Rayjean J
AU - Grankvist, Kjell
AU - Nøst, Therese H
AU - Imaz, Liher
AU - Chirlaque-López, María Dolores
AU - Johansson, Mikael
AU - Kaaks, Rudolf
AU - Martin, Richard M
AU - Kühn, Tilman
AU - McKay, James D
AU - Pala, Valeria
AU - Robbins, Hilary A
AU - Sandanger, Torkjel M
AU - Schibli, David
AU - Schulze, Matthias B
AU - Travis, Ruth C
AU - Vineis, Paolo
AU - Weiderpass, Elisabete
AU - Brennan, Paul
AU - Johansson, Mattias
AU - Richards, J Brent
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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.
AB - 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.
U2 - 10.1158/1055-9965.EPI-21-1033
DO - 10.1158/1055-9965.EPI-21-1033
M3 - Article
C2 - 35839461
SN - 1055-9965
VL - 31
SP - 1966
EP - 1974
JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
IS - 10
ER -