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

Environment International (Jan 2024)

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,
Ilja M. Nolte,
Bruce H.R. Wolffenbuttel,
Jana V. van Vliet-Ostaptchouk,
Harold Snieder

Affiliations

Xueling Lu: 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
Thomas P. van der Meer: Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Zoha Kamali: 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
Martijn van Faassen: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Ido P. Kema: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
André P. van Beek: Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Xijin Xu: Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 515041, Guangdong, China
Xia Huo: Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 510632, Guangdong, China
Alireza Ani: 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
Ilja M. Nolte: Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Bruce H.R. Wolffenbuttel: Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Jana V. van Vliet-Ostaptchouk: Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands
Harold Snieder: Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands; Corresponding author at: Department of Epidemiology, University Medical Center Groningen, Hanzeplein 1 9713 GZ, Groningen, the Netherlands.

Journal volume & issue: Vol. 183
p. 108396

Abstract

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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.

Published in Environment International

ISSN: 0160-4120 (Print)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/environment-international

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