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A Genome-Wide Association Study of 24-Hour Urinary Excretion of Endocrine Disrupting Chemicals Publisher Pubmed



Lu X1, 2 ; Van Der Meer TP3 ; Kamali Z1, 4 ; Van Faassen M5 ; Kema IP5 ; Van Beek AP3 ; Xu X2 ; Huo X6 ; Ani A1, 4 ; Nolte IM1 ; Wolffenbuttel BHR3 ; Van Vlietostaptchouk JV7 ; Snieder H1
Authors
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Authors Affiliations
  1. 1. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, Netherlands
  2. 2. Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Guangdong, 515041, China
  3. 3. Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, Netherlands
  4. 4. Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, 81746-7346, Iran
  5. 5. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, Netherlands
  6. 6. Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangdong, 510632, China
  7. 7. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, Netherlands

Source: Environment International Published:2024


Abstract

Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1. © 2023 The Authors
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