Comprehensive evaluation of the estrogen receptor alpha gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population.

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Human Genetics (Impact Factor: 4.52). 05/2008; 123(4):333-41. DOI: 10.1007/s00439-008-0482-z
Source: PubMed

ABSTRACT We previously investigated the estrogen receptor alpha gene (ESR1) as a positional candidate for type 2 diabetes (T2DM), and found evidence for association between the intron 1-intron 2 region of this gene and T2DM and/or nephropathy in an African American (AA) population. Our objective was to comprehensively evaluate variants across the entire ESR1 gene for association in AA with T2DM and end stage renal disease (T2DM-ESRD). One hundred fifty SNPs in ESR1, spanning 476 kb, were genotyped in 577 AA individuals with T2DM-ESRD and 596 AA controls. Genotypic association tests for dominant, additive, and recessive models, and haplotypic association, were calculated using a chi(2) statistic and corresponding P value. Thirty-one SNPs showed nominal evidence for association (P < 0.05) with T2DM-ESRD in one or more genotypic model. After correcting for multiple tests, promoter SNP rs11964281 (nominal P = 0.000291, adjusted P = 0.0289), and intron 4 SNPs rs1569788 (nominal P = 0.000754, adjusted P = 0.0278) and rs9340969 (nominal P = 0.00109, adjusted P = 0.0467) remained significant at experimentwise error rate (EER) P </= 0.05 for the dominant class of tests. Twenty-three of the thirty-one associated SNPs cluster within the intron 4-intron 6 regions. Gender stratification revealed nominal evidence for association with 35 SNPs in females (352 cases; 306 controls) and seven SNPs in males (225 cases; 290 controls). We have identified a novel region of the ESR1 gene that may contain important functional polymorphisms in relation to susceptibility to T2DM and/or diabetic nephropathy.

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Available from: Donald W Bowden, Aug 04, 2014
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    • "Estrogen has shown to have antidiabetic actions in both rodent models as well as clinical trials (Louet et al. 2004; Margolis et al. 2004; Seed 2002) . Our association results suggest a differential association with ESR1 variants and T2DM-ESRD in males (7 SNPs) versus females (35 SNPs) (Keene et al 2008b). "
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    ABSTRACT: Genetic variation of the estrogen receptor alpha (ESR1) and beta (ESR2) has been associated with components of the metabolic syndrome. The relationships of two ESR1 (rs2234693 and rs9340799) and three ESR2 (rs1271572, rs1256049, and rs4986938) polymorphisms with the metabolic syndrome were examined in 532 Caucasian female participants (median age 63.1 years) in the Women's Health Study. Most women (99.1%) were postmenopausal. The associations between ESR1 and ESR2 genotypes and haplotypes with the metabolic syndrome were evaluated. Effect modification by hormone therapy was also assessed. Genotype and haplotype distributions were similar between women with and without metabolic syndrome. We found no consistent associations between the genotypes and haplotypes tested and the metabolic syndrome, or its components, in logistic regression models. No effect modification by hormone therapy use was noted. No association between these genetic variants in ESR1 and ESR2 and the metabolic syndrome was observed among these Caucasian women. Further investigation regarding the potential involvement of estrogen receptor genes and the metabolic syndrome may be warranted in other ethnic groups.
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