Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology

Galán, José Jorge; Buch, Belén; Cruz, Natalio; Segura, Ana; Morón, Francisco Jesús; Bassas, Lluís; Martínez‐Piñeiro, Luis; Real, Luis Miguel; Ruiz, Agustı́n

doi:10.1016/j.fertnstert.2005.03.070

Cited by 45 publications

(43 citation statements)

References 36 publications

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“…Minor allele homozygotes of rs4870056, rs2234693, and rs7774230 have increased S i (Table 4). Because ER-␣ has pleiotropic influences, including effects on reproductive fitness (26), common "risk" alleles may have been retained in the population due to positive selective pressure unrelated to their effect on the metabolic phenotypes investigated. Alternatively, common major alleles of rs2431260 and rs2175898, associated with increased BMI and waist circumference (Table 4), may reflect past selection pressures favoring high-energy storage.…”

Section: Discussionmentioning

confidence: 99%

Association of the Estrogen Receptor-α Gene With the Metabolic Syndrome and Its Component Traits in African-American Families

et al. 2007

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OBJECTIVE-We previously detected an association between a region of the estrogen receptor-␣ (ESR1) gene and type 2 diabetes in an African-American case-control study; thus, we investigated this region for associations with the metabolic syndrome and its component traits in African-American families from the Insulin Resistance Atherosclerosis Family Study. RESEARCH DESIGN AND METHODS-A total of 17 single nucleotide polymorphisms (SNPs) from a contiguous 41-kb intron 1-intron 2 region of the ESR1 gene were genotyped in 548 individuals from 42 African-American pedigrees. Generalized estimating equations were computed using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation.RESULTS-Significant associations were detected between ESR1 SNPs and the metabolic syndrome (P ϭ 0.005 to P ϭ 0.029), type 2 diabetes (P ϭ 0.001), insulin sensitivity (P ϭ 0.0005 to P ϭ 0.023), fasting insulin (P ϭ 0.022 to P ϭ 0.033), triglycerides (P ϭ 0.021), LDL (P ϭ 0.016 to P ϭ 0.034), cholesterol (P ϭ 0.046), BMI (P ϭ 0.016 to P ϭ 0.035), waist circumference (P ϭ 0.012 to P ϭ 0.023), and subcutaneous adipose tissue area (P ϭ 0.016).CONCLUSIONS-It appears likely that ESR1 contributes to type 2 diabetes and CVD risk via pleiotropic effects, leading to insulin resistance, a poor lipid profile, and obesity. Diabetes 56: 2135-2141, 2007

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Section: Discussionmentioning

confidence: 99%

Association of the Estrogen Receptor-α Gene With the Metabolic Syndrome and Its Component Traits in African-American Families

et al. 2007

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“…Given the relatively low frequencies of the associated protective alleles and haplotypes, the contribution of this gene to diabetes risk is likely to be relatively modest; however, this may be the model for most diabetes loci, and the influence of this locus may be greater in the context of epistatic or environmental interactions. Estrogen receptor-␣ has pleiotropic influences, including effects on reproductive fitness (53), so these uncommon alleles may have been retained in the population because of positive selective pressure unrelated to diabetes or ESRD.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Estrogen Receptor-α Gene With Type 2 Diabetes and/or Nephropathy in African-American and European-American Populations

et al. 2007

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The estrogen receptor-␣ gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P ‫؍‬ 0.013, admixture-adjusted P a ‫؍‬ 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P ‫؍‬ 0.004, P a ‫؍‬ 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P a < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 EuropeanAmerican type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P ‫؍‬ 0.015) and rs1709183 (P ‫؍‬ 0.019), and a four-SNP haplotype containing these SNPs (P ‫؍‬ 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk. Diabetes 56:675-684, 2007

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“…The discrepancy between the Italian and the Japanese study may be related to genuine ethnic differences and/or different environmental conditions. A role for ESR2 gene SNP in male infertility has also been proposed recently (Aschim et al, 2005;Galan et al, 2005). Given that for each type of variant and haplotype there are only sporadic studies, it is important to confirm their clinical significance in other independent study populations.…”

Section: Oestrogen Receptormentioning

confidence: 94%

Gene polymorphisms/mutations relevant to abnormal spermatogenesis

Nuti¹,

Krausz²

2008

Reproductive BioMedicine Online

139

110

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Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology

Cited by 45 publications

References 36 publications

Association of the Estrogen Receptor-α Gene With the Metabolic Syndrome and Its Component Traits in African-American Families

Association of the Estrogen Receptor-α Gene With the Metabolic Syndrome and Its Component Traits in African-American Families

Investigation of the Estrogen Receptor-α Gene With Type 2 Diabetes and/or Nephropathy in African-American and European-American Populations

Gene polymorphisms/mutations relevant to abnormal spermatogenesis

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