Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Environment international, 2024-01, Vol.183, p.108396-108396, Article 108396

Ort / Verlag

Netherlands: Elsevier Ltd

Erscheinungsjahr

2024

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• [Display omitted] •Unique genome-wide association study of multiple EDCs in 24-hour urine.•Four independent SNPs associated with EDCs through multi-trait GWAS analysis.•SNPs in CYP450 and SLC genes associated with MECPP and MEHHP.•CYP2C9 and SLC17A1 likely play causal roles in phthalate metabolism and excretion. 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.