Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias

S, Ban; Sata, Fumihiro; Kurahashi, Norie; Kasai, Setsuko; Moriya, Kyoji; Κakizaki, Hidehiro; Nonomura, Katsuya; Kishi, Reiko

doi:10.1093/humrep/den098

Cited by 48 publications

(36 citation statements)

References 21 publications

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“…Previously, polymorphic ESR2 variants have been associated with milder variations in sexual development such as hypospadias and micropenis, [25][26][27][28][29] and a heterozygous ESR2 variant c.1295C > A leading to a missense change p.…”

Section: Discussionmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

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Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

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Section: Discussionmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

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“…The AGAGA haplotype of the estrogen receptor 1 (ESR1) gene is strongly associated with hypospadias [117]. The ESR1 C-A haplotype, for ESR1 XbaI and ESR2 2681-4A>G, respectively, increases the risk of malformation, as well [118]. An increased number of CA repeats (and subsequently increased ER activity) also augments the risk of malformation [119], and more recently we identified ATF3 polymorphisms in patients with isolated hypospadias [120].…”

Section: Iii-2-2 Gene Polymorphismsmentioning

confidence: 90%

Hypospadias: Interactions between environment and genetics

Kalfa

Philibert

Baskin

et al. 2011

Molecular and Cellular Endocrinology

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“…[13][14] Both our study, and other previous studies have identified that genetic variants for ESR1 and ESR2 could raise the susceptibility of CO and HS by enhancing the effects of estrogenic EEDs, which are known as xenoestrogens and currently the largest group of known EEDs. 7,15 In addition, several nuclear receptors, such as aryl-hydrocarbon receptor (AHR) and pregnane X receptor (PXR or NR1I2), are known to be crucial for EED-mediated CYP transcription. 16 Previous studies have reported that polymorphisms in AHR may affect AHR functions, notably the induction of CYP1 genes, suggesting a potential role for nuclear receptor polymorphisms in the variable responses to xenobiotic chemicals.…”

Section: Introductionmentioning

confidence: 99%

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

et al. 2012

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We hypothesized that single-nucleotide polymorphisms (SNPs) of genes involved in environmental endocrine disruptors (EEDs) metabolism might influence the risk of male genital malformations. In this study, we explored for association between 384 SNPs in 15 genes (AHR, AHRR, ARNT, ARNT2, NR1I2, RXRA, RXRB, RXRG, CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP3A4, CYP17A1 and CYP19A1) and risk of cryptorchidism (CO) and hypospadias (HS) in 334 Japanese (JPN) males (141 controls, 95 CO and 98 HS) and 187 Italian (ITA) males (129 controls and 58 CO). In the JPN study group, five SNPs from ARNT2 (rs2278705 and rs5000770), CYP1A2 (rs2069521), CYP17A1 (rs4919686) and NR1I2 (rs2472680) were significantly associated at both allelic and genotypic levels with risk of at least one genital malformation phenotype. In the ITA study group, two SNPs in AHR (rs3757824) and ARNT2 (rs1020397) were significantly associated with risk of CO. Interaction analysis of the positive SNPs using multifactor dimensionality reduction demonstrated that synergistic interaction between rs2472680, rs4919686 and rs5000770 had 62.81% prediction accuracy for CO (P ¼ 0.011) and that between rs2069521 and rs2278705 had 69.98% prediction accuracy for HS (P ¼ 0.001) in JPN population. In a combined analysis of JPN and ITA population, the most significant multi-locus association was observed between rs5000770 and rs3757824, which had 65.70% prediction accuracy for CO (P ¼ 0.055). Our findings indicate that genetic polymorphisms in genes involved in EED metabolism are associated with risk of CO and HS.

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Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias

Abstract: These findings suggest that the G allele containing variants of ESR1 XbaI and the G allele containing variants of ESR2 2681-4A>G may decrease the risk of hypospadias, whereas the ESR1 C-A haplotype may increase its risk.

Cited by 48 publications

References 21 publications

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Hypospadias: Interactions between environment and genetics

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

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