Common genetic variants associated with urinary phthalate levels in children: A genome-wide study

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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.

References: Mariona Bustamante, Laura Balagué-Dobón, Zsanett Buko, Amrit Kaur Sakhi, Maribel Casas, Lea Maitre, Sandra Andrusaityte, Regina Grazuleviciene, Kristine B. Gützkow, Anne-Lise Brantsæter, Barbara Heude, Claire Philippat, Leda Chatzi, Marina Vafeiadi, Tiffany C. Yang, John Wright, Amy Hough, Carlos Ruiz-Arenas, Ramil N. Nurtdinov, Geòrgia Escaramís, Juan R. González, Cathrine Thomsen, Martine Vrijheid, Common genetic variants associated with urinary phthalate levels in children: A genome-wide study, Environment International, Volume 190, 2024, 108845, ISSN 0160-4120, https://doi.org/10.1016/j.envint.2024.108845.

Details:

Author(s):

Mariona Bustamante, Laura Balagué-Dobón, Zsanett Buko, Amrit Kaur Sakhi, Maribel Casas, Lea Maitre, Sandra Andrusaityte, Regina Grazuleviciene, Kristine B. Gützkow, Anne-Lise Brantsæter, Barbara Heude, Claire Philippat h, Leda Chatzi, Marina Vafeiadi, Tiffany C. Yang, John Wright, Amy Hough, Carlos Ruiz-Arenas, Ramil N. Nurtdinov, Geòrgia Escaramís & Martine Vrijheid

Director

Principal Research Fellow

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