Background: Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem. Inter-individual susceptibility to the adverse effects of EDCs may partly be attributed to genetic polymorphisms of metabolic enzymes.
Objectives: We aimed to examine the whole genome to identify genetic factors predisposing individuals to higher EDC concentrations and higher risk of EDC-associated diseases.
Methods: A genome-wide association study (GWAS) for 24-hour urinary excretions of 15 EDCs (including four parabens, two bisphenols, and nine phthalate metabolites) was performed in 652 participants from a Lifelines sub-cohort (Cyto1). Additionally, we conducted three multi-trait analyses of GWAS (MTAG) to boost statistical power and exploit the shared information in the three classes of EDCs. Two other, independent Lifelines sub-cohorts (Cyto2 and GSA, n=433 samples in total) were used for replication and the three samples were meta-analyzed for the suggestively associated single nucleotide polymorphisms (SNPs). Next, we calculated the proportion of EDCs’ variance explained by the identified SNPs. Finally, bioinformatics analyses and eQTL analyses were used to functionally annotate the findings.
Results: We identified five genome-wide significant, independent SNPs (p-value < 5x10-8) representing four independent signals associated with phthalate metabolites MECPP and MEHHP. Three of the four independent 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. Two SNPs (rs1359232 and rs4918798) have been previously reported to be associated with metabolism of various other substances such as serum uric acid levels and warfarin. In silico annotation and eQTL analyses supported a likely causal role of CYP2C9, SLC17A1 and SLC17A4 in metabolism and excretion of MECPP and MEHHP.
Conclusions: Urinary excretions of MEHHP and MECPP were associated with genetic variants in CYP and SLC genes, providing biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9, SLC17A1 and SLC17A4.
Keywords: Endocrine disruptor, metabolism, excretion, solute carrier, cytochrome P450, SNP, genome-wide association study