Common genetic variants associated with urinary phthalate levels in children: A genome-wide study
2024
Bustamante, Mariona | Balagué-Dobón, Laura | Buko, Zsanett | Sakhi, Amrit, Kaur | Casas, Maribel | Maitre, Lea | Andrusaityte, Sandra | Grazuleviciene, Regina | Gützkow, Kristine, B | Brantsæter, Anne-Lise | Heude, Barbara | Philippat, Claire | Chatzi, Leda | Vafeiadi, Marina | Yang, Tiffany, C | Wright, John | Hough, Amy | Ruiz-Arenas, Carlos | Nurtdinov, Ramil, N | Escaramís, Geòrgia | González, Juan, R | Thomsen, Cathrine | Vrijheid, Martine | Environment and Health Over the Lifecourse, ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain | Environment and Health Over the Lifecourse, ISGlobal, Barcelona, Spain | Department of Oncological Science, Huntsman Cancer Institute, Salt Lake City, United States | Norwegian Institute of Public Health [Oslo] (NIPH) | Department of Environmental Science, Vytautas Magnus University, 44248 Kaunas, Lithuania | Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques (CRESS (U1153 / UMR_A 1125)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Épidémiologie environnementale appliquée au développement et à la santé respiratoire/Environmental Epidemiology applied to Development and Respiratory Health (EPIDER (ENEDER) - IAB) ; Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) | Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States | Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece | Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR) | Computational Biology Program, CIMA University of Navarra, idiSNA, Pamplona 31008, Spain | Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Catalonia, Spain | CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Departament de Biomedicina, Institut de Neurociències, Universitat de Barcelona (UB), Barcelona, Spain
International audience
Mostrar más [+] Menos [-]Inglés. Introduction: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes.Objective: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS).Methods: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool.Results: We identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion.Conclusion: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.
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