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

Qin, Xian‐Yang; Kojima, Yoshiyuki; Mizuno, Kentaro; Ueoka, Katsuhiko; Massart, Francesco; Spinelli, Claudio; Zaha, Hiroko; Okura, Masahiro; Yoshinaga, Jun; Yonemoto, Junzo; Kohri, Kenjiro; Hayashi, Yutaro; Ogata, Tsutomu; Sone, Hirohito

doi:10.1038/jhg.2012.48

Cited by 33 publications

(25 citation statements)

References 46 publications

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“…For example an (albeit un-replicated) association reported by Qin et al, 201 was with a variant of the Aryl hydrocarbon receptor nuclear translocator 2 ( ARNT2 ) gene (OR for minor homozygous genotype rs5000770 [AA vs. GG]: 3.5, 95% CI 1.7–7.3). This gene is part of a family of transcription factors that, among other roles, regulates several physiological pathways including responses to environmental contaminants.…”

Section: Geneticsmentioning

confidence: 99%

Risk factors for cryptorchidism

et al. 2017

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The condition known as cryptorchidism – undescended testis – is one of the most common congenital abnormalities found among males, and is one of the few known risk factors for testicular cancer (TC). Like testicular cancer, the key exposures in the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases – between 8–15 weeks and 25–35 weeks gestation – and while it is clear that a failure of testes to descend permanently is likely due to disruptions to one or both of these phases, the cause(s) and mechanism(s) of such disruption are still unclear. In this manuscript, we review the broad range of putative risk factors that have been evaluated in relation to the development of cryptorchidism to date, discuss their plausibility, and make suggestions regarding further approaches to understand aetiology. There are few exposures for which there is consistent evidence of an association with cryptorchidism; and in those cases where evidence appears unequivocal – for example, the relationship between cryptorchidism and gestational measures such as low birth weight – the measured exposure is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor may vary considerably between mother/son pairs depending on an array of genetic, maternal, placental and foetal factors – all of which could vary between regions.

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Section: Geneticsmentioning

confidence: 99%

Risk factors for cryptorchidism

et al. 2017

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“…Interaction analysis for the positive SNPs indicated possible synergic interactions between SNPs in ARNT2 and those in the four other genes in the predisposition for CO or HS. 6 These results indicate that complex gene-gene and gene-environmental interactions constitute risk factors for EED-induced genital abnormalities. Nevertheless, the mechanisms by which the SNPs identified in the present study increase the risk of genital abnormalities still need to be elucidated.…”

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confidence: 90%

“…7 Thus, the results of this study imply that specific alleles of genes involved in the dioxin signaling pathway confer genetic susceptibility to EEDs, and thereby lead to undermasculinized genitalia. This notion is consistent with previous studies by Fujita et al 8 and Soneda et al 9 showing a significant association between the presence of micropenis, a phenotype of undermasculinization, and a SNP in AHRR encoding AHR repressor that is a component of a negative feedback loop in the dioxin-AHR signaling pathway.Qin et al 6 found that SNPs in CYP1A2, NR1I2 and CYP17A1 are also associated with the risk of CO and/or HS. Of these, CYP1A2 and NR1I2 are involved in EED metabolism, and CYP17A1 encodes one of the key enzymes for estrogen biosynthesis.…”

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confidence: 99%

“…In this issue of the Journal, Qin et al 6 report an association between single-nucleotide polymorphisms (SNPs) in genes involved in EED metabolism and the risk of CO and HS. They examined 384 SNPs of 15 genes in 334 Japanese male subjects (95 patients with CO, 98 patients with HS and 141 unaffected controls) and 187 Italian male subjects (58 patients with CO and 129 controls), and identified SNPs in 5 genes that were over-represented in the patient group(s) in comparison with the control group.…”

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confidence: 99%

“…Qin et al 6 found that SNPs in CYP1A2, NR1I2 and CYP17A1 are also associated with the risk of CO and/or HS. Of these, CYP1A2 and NR1I2 are involved in EED metabolism, and CYP17A1 encodes one of the key enzymes for estrogen biosynthesis.…”

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

Fukami

2012

J Hum Genet

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C ryptorchidism (CO) and hypospadias (HS) are common congenital abnormalities that affect B1% of full-term male newborns. 1-3 CO and HS usually occur as multifactorial traits subject to a number of genetic and environmental factors with relatively minor effects, although in rare cases these conditions can occur as monogenic disorders because of mutations in genes such as AR and SRD5A2. 2,3 During the last few decades, the prevalence of undermasculinized male genitalia, including HS and CO, has increased in several countries. 4 Similarly, compromised male reproductive function has recently been documented in various wildlife species. 5 The rapid increase in the prevalence of undermasculinized genitalia indicates that intrauterine exposure to environmental chemicals with endocrine-disrupting properties (environmental endocrine disruptors (EEDs)) has a role in the development of such abnormalities, because large quantities of EEDs have been released into the environment in recent decades. 5 Consistent with this notion, studies on laboratory animals have shown that intrauterine and lactational exposure to EEDs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, affects the reproductive system of male offsprings. 1,5 The effect of EEDs on male reproductive organs appears to depend on the susceptibility of the individual, in addition to the dosage and types of EEDs and the developmental stages of exposure. Till date, several association studies have been performed for patients with CO and HS, in order to identify genetic variants that predispose individuals to these conditions. 2,3 Consequently, polymorphisms in several genes, such as AR, ESR1, ESR2 and SRD5A2, have been identified as the disease-associated variants. 2,3 However, polymorphisms in genes involved in EED metabolism have been poorly investigated in patients with CO and HS.In this issue of the Journal, Qin et al. 6 report an association between single-nucleotide polymorphisms (SNPs) in genes involved in EED metabolism and the risk of CO and HS. They examined 384 SNPs of 15 genes in 334 Japanese male subjects (95 patients with CO, 98 patients with HS and 141 unaffected controls) and 187 Italian male subjects (58 patients with CO and 129 controls), and identified SNPs in 5 genes that were over-represented in the patient group(s) in comparison with the control group. Notably, a significant association was found between SNPs in the aryl hydrocarbon receptor nuclear translocator 2 gene (ARNT2) and the risk of CO and HS in both the Japanese and Italian groups. Furthermore, a SNP in the aryl hydrocarbon receptor gene (AHR) was found to be associated with CO in the Italian group. In this regard, it is noteworthy that both ARNT2 and AHR have been implicated in the dioxin signaling pathway. 1,7 In the cytoplasm, dioxins bind to AHR and the ligand-bound AHR dimerizes with ARNT. The ligand-activated AHR-ARNT heterodimer then transactivates several target genes and modulates estrogen receptor signaling. 1 ARNT2 has homology with ARNT and is predicted to interact with AHR. 7 ...

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Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Lagergren

Cook

et al. 2015

Intl Journal of Cancer

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The strong male predominance in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study (VEGAS). This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients, and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p=0.002) and in males (p=0.003), but not in females separately (p=0.3). This association was found in tobacco smokers (p=0.003), and in BE patients without reflux (p=0.004), but not in non-smokers (p=0.2) or those with reflux (p=0.036). SNPs within JMJD1C were associated with risk of EAC in females (p=0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC, or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

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

Cited by 33 publications

References 46 publications

Risk factors for cryptorchidism

Risk factors for cryptorchidism

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

Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

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