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

Summary: GWAS identifies genetic variants in CYP2C9 and SLC17A1 linked to phthalate metabolism, explaining 8-9% of variance. #EndocrineDisruptors #Genomics

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

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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