Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-? Gene with Postmenopausal Osteoporosis

Abstract

We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-alpha (ERalpha) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups--with vertebral or femoral osteoporosis (n = 106) or without osteoporosis (n = 122)--according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49-4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89-0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08-1.19). In a multiple linear regression model, L2-L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERalpha is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3'-untranslated region of the ERalpha gene which may participate in the regulation of ERalpha gene expression remains to be determined.

Molecular studies of identification of genes for osteoporosis: the 2002 update

“…Among them, the T<C and the A<G in intron 1 and the TA repeat in the promoter region are those most frequently studied. Novel polymorphisms are continuously being identified and tested for association; recent examples include codon 325 (CCC<CCG) (Jurada et al 2001), T262C of exon 1 (Ongphiphadhanakul et al 2001a), G2014A of exon 8 (Ongphiphadhanakul et al 2001b), and G261C of exon 1 (Langdahl et al 2000b).…”

Association of the G2014G Genotype in Estrogen Receptor 1 Gene with Failure of the Mifepristone-Induced Termination of Early Pregnancy

“…It should be noted that G2014A is a silent polymorphism that does not alter the amino acid sequence, which might be explained by the linkage disequilibrium between G2014A with and regulatory sequences in the 3'UTR of the ESR1 gene (Ongphiphadhanakul et al 2001(Ongphiphadhanakul et al , 2003(Ongphiphadhanakul et al , 2005. Specifically, both 5'and 3'UTR have been reported to play an important role in the regulation of gene expression.…”

“…Conversely, the sensitivity to mifepristone decreased in the subjects with the G allele, as they failed in medical abortion. The G2014A polymorphism is associated with post-menopausal osteoporosis, bone mineral density in postmenopausal and breast cancer, all of which are hormone-dependent diseases (Curran et al 2001;Ongphiphadhanakul et al 2001Ongphiphadhanakul et al , 2003. The frequency of the A allele is higher than that of the G allele in osteoporosis (Ongphiphadhanakul et al 2001(Ongphiphadhanakul et al , 2003.…”

“…The G2014A polymorphism is associated with post-menopausal osteoporosis, bone mineral density in postmenopausal and breast cancer, all of which are hormone-dependent diseases (Curran et al 2001;Ongphiphadhanakul et al 2001Ongphiphadhanakul et al , 2003. The frequency of the A allele is higher than that of the G allele in osteoporosis (Ongphiphadhanakul et al 2001(Ongphiphadhanakul et al , 2003. The frequency of the G allele is higher than that of the A allele in breast cancer population; a subject has approximately a three-fold increase in the risk of developing breast cancer, if she does not express the AA genotype (Curran et al 2001).…”

Association of transforming growth factor (TGF) p1 T(861-20)C polymorphism with bone mineral density and TGFip gene expression in postmenopausal osteoporosis

“…Кроме того, TФР β1 считает-ся медиатором действия эстрогенов на костную ткань [16] при апоптозе остеокластов, что приводит к уменьше-нию резорбции кости [17]. В то же время пониженные концентрации TФР β1 вследствие недостатка эстрогенов могут благоприятствовать развитию ОП у женщин в постменопаузе [18,19].…”