Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.
Journal
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
ISSN: 1538-7755
Titre abrégé: Cancer Epidemiol Biomarkers Prev
Pays: United States
ID NLM: 9200608
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
received:
02
09
2021
revised:
09
12
2021
accepted:
13
07
2022
pubmed:
16
7
2022
medline:
6
10
2022
entrez:
15
7
2022
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 35839461
pii: 707037
doi: 10.1158/1055-9965.EPI-21-1033
pmc: PMC9530646
mid: NIHMS1825520
doi:
Substances chimiques
Biomarkers, Tumor
0
3-methylbutyrylcarnitine
31023-24-2
Carnitine
S7UI8SM58A
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1966-1974Subventions
Organisme : NCI NIH HHS
ID : U19 CA203654
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : CIHR
Pays : Canada
Organisme : Cancer Research UK
ID : C18281/A29019
Pays : United Kingdom
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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