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
  • 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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