Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study
Marta Galvez-Fernandez,
Francisco Sanchez-Saez,
Arce Domingo-Relloso,
Zulema Rodriguez-Hernandez,
Sonia Tarazona,
Vannina Gonzalez-Marrachelli,
Maria Grau-Perez,
Jose M. Morales-Tatay,
Nuria Amigo,
Tamara Garcia-Barrera,
Jose L. Gomez-Ariza,
F. Javier Chaves,
Ana Barbara Garcia-Garcia,
Rebeca Melero,
Maria Tellez-Plaza,
Juan C. Martin-Escudero,
Josep Redon,
Daniel Monleon
Affiliations
Marta Galvez-Fernandez
Department of Preventive Medicine and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain; Department of Preventive Medicine, Hospital Universitario Severo Ochoa, Madrid, Spain; Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain
Francisco Sanchez-Saez
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Department of Statistics and Operational Research, University of Valencia, Valencia, Spain
Arce Domingo-Relloso
Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain; Department of Statistics and Operational Research, University of Valencia, Valencia, Spain; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, USA
Zulema Rodriguez-Hernandez
Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain; Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain
Sonia Tarazona
Applied Statistics and Operations Research and Quality Politècnica de València, Valencia, Spain
Vannina Gonzalez-Marrachelli
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain
Maria Grau-Perez
Department of Preventive Medicine and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain; Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Department of Statistics and Operational Research, University of Valencia, Valencia, Spain
Jose M. Morales-Tatay
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Department of Pathology University of Valencia, Valencia, Spain
Nuria Amigo
Biosfer Teslab, Reus, Spain; Department of Basic Medical Sciences, University Rovira I Virgili, Reus, Spain; Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
Tamara Garcia-Barrera
Research Center for Natural Resources, Health and the Environment (RENSMA), Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain
Jose L. Gomez-Ariza
Research Center for Natural Resources, Health and the Environment (RENSMA), Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain
F. Javier Chaves
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
Ana Barbara Garcia-Garcia
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain
Rebeca Melero
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain
Maria Tellez-Plaza
Department of Preventive Medicine and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain; Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain; Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Corresponding author. Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Melchor Fernandez Almagro, 5, 28029, Madrid, Spain.
Juan C. Martin-Escudero
Department of Internal Medicine, Hospital Universitario Rio Hortega, University of Valladolid, Valladolid, Spain
Josep Redon
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain
Daniel Monleon
Institute for Biomedical Research, Hospital Clinic of Valencia (INCLIVA), Valencia, Spain; Department of Pathology University of Valencia, Valencia, Spain; Center for Biomedical Research Network on Frailty and Health Aging (CIBERFES), Madrid, Spain
Background: Limited studies have evaluated the joint influence of redox-related metals and genetic variation on metabolic pathways. We analyzed the association of 11 metals with metabolic patterns, and the interacting role of candidate genetic variants, in 1145 participants from the Hortega Study, a population-based sample from Spain. Methods: Urine antimony (Sb), arsenic, barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V), and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured by ICP-MS and AAS, respectively. We summarized 54 plasma metabolites, measured with targeted NMR, by estimating metabolic principal components (mPC). Redox-related SNPs (N = 291) were measured by oligo-ligation assay. Results: In our study, the association with metabolic principal component (mPC) 1 (reflecting non-essential and essential amino acids, including branched chain, and bacterial co-metabolism versus fatty acids and VLDL subclasses) was positive for Se and Zn, but inverse for Cu, arsenobetaine-corrected arsenic (As) and Sb. The association with mPC2 (reflecting essential amino acids, including aromatic, and bacterial co-metabolism) was inverse for Se, Zn and Cd. The association with mPC3 (reflecting LDL subclasses) was positive for Cu, Se and Zn, but inverse for Co. The association for mPC4 (reflecting HDL subclasses) was positive for Sb, but inverse for plasma Zn. These associations were mainly driven by Cu and Sb for mPC1; Se, Zn and Cd for mPC2; Co, Se and Zn for mPC3; and Zn for mPC4. The most SNP-metal interacting genes were NOX1, GSR, GCLC, AGT and REN. Co and Zn showed the highest number of interactions with genetic variants associated to enriched endocrine, cardiovascular and neurological pathways. Conclusions: Exposures to Co, Cu, Se, Zn, As, Cd and Sb were associated with several metabolic patterns involved in chronic disease. Carriers of redox-related variants may have differential susceptibility to metabolic alterations associated to excessive exposure to metals.
