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

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; Lifelines Cohort Study; Ilja M Nolte; Bruce H R Wolffenbuttel; Jana V van Vliet-Ostaptchouk; Harold Snieder

doi:10.1016/j.envint.2023.108396

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

Environ Int. 2024 Jan:183:108396. doi: 10.1016/j.envint.2023.108396. Epub 2023 Dec 20.

Affiliations

¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands; Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 515041, Guangdong, China.
² Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands.
³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands; Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan 81746-7346, Iran.
⁴ Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands.
⁵ Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 515041, Guangdong, China.
⁶ Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 510632, Guangdong, China.
⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands.
⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands.
⁹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands. Electronic address: h.snieder@umcg.nl.

PMID: 38150807
DOI: 10.1016/j.envint.2023.108396

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, p_MECPP = 5.38x10^-25; rs117033379, p_MECPP = 1.96x10^-19; rs4918798, p_MECPP = 4.01x10^-71; rs7895726, p_MEHHP = 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, p_MECPP = 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.

Keywords: Endocrine disruptor; Excretion; Genome-wide association study; Metabolism; Solute carrier; cytochrome P450.

MeSH terms

Cytochrome P-450 CYP2C9
Endocrine Disruptors* / urine
Environmental Exposure
Environmental Pollutants* / urine
Genome-Wide Association Study
Humans
Phthalic Acids* / urine

Substances

phthalic acid
Endocrine Disruptors
Cytochrome P-450 CYP2C9
Phthalic Acids
Environmental Pollutants