A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals

Lifelines Cohort Study, Xueling Lu, Thomas P. van der Meer, Zoha Kamali, Martijn van Faassen, Ido P. Kema, André P. van Beek, Xijin Xu, Xia Huo, Alireza Ani, Ilja M. Nolte, Bruce H.R. Wolffenbuttel, Jana V. van Vliet-Ostaptchouk, Harold Snieder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number108396
Number of pages10
JournalEnvironment international
Volume183
DOIs
Publication statusPublished - Jan-2024

Keywords

  • cytochrome P450
  • Endocrine disruptor
  • Excretion
  • Genome-wide association study
  • Metabolism
  • Solute carrier

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