2. Academic Validation
  3. Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements

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. doi: 10.1158/1055-9965.EPI-21-1033.
Karl Smith-Byrne # 1,  Agustin Cerani # 2,  Florence Guida 1,  Sirui Zhou 2,  Antonio Agudo 3,  Krasimira Aleksandrova 4 5,  Aurelio Barricarte 6 7,  Miguel Rodríguez Barranco 7 8 9,  Christoph H Bochers 2 10,  Inger Torhild Gram 11,  Jun Han 10,  Christopher I Amos 12,  Rayjean J Hung 13,  Kjell Grankvist 14,  Therese Haugdhal Nøst 11,  Liher Imaz 15 16,  María Dolores Chirlaque-López 7 17,  Mikael Johansson 18,  Rudolf Kaaks 19 20,  Tilman Kühn 19,  Richard M Martin 21,  James D McKay 1,  Valeria Pala 22,  Hilary A Robbins 1,  Torkjel M Sandanger 11,  David Schibli 10,  Matthias B Schulze 4 5,  Ruth C Travis 23,  Paolo Vineis 24,  Elisabete Weiderpass 1,  Paul Brennan 1,  Mattias Johansson 1,  J Brent Richards 2 25 26
Affiliations

Affiliations

  • 1 Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • 2 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada/Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
  • 3 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, Spain.
  • 4 Nutrition, Immunity and Metabolism Senior Scientist Group, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
  • 5 University of Potsdam, Institute of Nutritional Science, Potsdam, Germany.
  • 6 Navarra Institute for Health Research (IdiSNA) Pamplona, Spain.
  • 7 CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • 8 Escuela Andaluza de Salud Pública (EASP), Granada, Spain.
  • 9 Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
  • 10 University of Victoria-Genome British Columbia Proteomics Centre, Victoria, BC, Canada/Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
  • 11 Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Norway.
  • 12 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
  • 13 Prosserman Centre for Health Research, Mount Sinai Hospital, Toronto, Canada.
  • 14 Department of Medical Biosciences, Umeå University, Umeå, Sweden.
  • 15 Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Donostia-San Sebastian, Spain.
  • 16 Biodonostia Health Research Institute, Donostia-San Sebastian, Spain.
  • 17 Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
  • 18 Department of Radiation Sciences, Umeå University, Umeå, Sweden.
  • 19 German Cancer Research Center (DKFZ), Heidelberg, Department of Cancer Epidemiology.
  • 20 Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
  • 21 Clinical Epidemiology & Public Health, University of Bristol, Bristol, United Kingdom.
  • 22 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano.
  • 23 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
  • 24 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
  • 25 Division of Endocrinology, Department of Medicine & Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • 26 Department of Twin Research and Genetic Epidemiology, King's College London, Strand, London, United Kingdom.
  • # Contributed equally.
PMID: 35839461 DOI: 10.1158/1055-9965.EPI-21-1033
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.

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