RESUMO
Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women, but some women are resistant to therapy. A recently reported case of severe estrogen resistance caused by a germline mutation at the estrogen receptor (ER) gene locus suggests the possibility that other variants of the ER gene could be responsible for resistance to HRT and could also be an answer to the heritable components of bone density. Three restriction fragment length polymorphisms (RFLPs) at the ER gene locus, represented as BstUI (or B variant), PvuII, and XbaI, and their relationship to bone mineral density (BMD) and estrogen responsiveness to HRT were examined in 248 healthy postmenopausal women, aged 41-68 yr (mean +/- SD, 52.0 +/- 4.6 yr) in Korea. The BstUI restriction site was not found in Korean women. The distribution of the PvuII and XbaI RFLPs was as follows: PP, 35 (14.1%); Pp, 136 (54.8%); pp, 77 (31.1%) and XX, 18 (7.3%); Xx, 72 (29.0%); and xx, 158 (63.7%), respectively (capital letters signify the absence of and lower case letters signify the presence of the restriction site of each RFLP). There was no significant relation between ER genotypes and z score values of lumbar spine BMD. Also, no significant genotypic differences were found in the change in lumbar spine BMD and those in biochemical markers before and after 1 yr of HRT. These data indicate no significant effects of ER genotypes on BMD and estrogen responsiveness after HRT.
Assuntos
Densidade Óssea , Terapia de Reposição de Estrogênios , Pós-Menopausa , Receptores de Estrogênio/genética , Adulto , Idoso , Sequência de Bases , Biomarcadores , Feminino , Genótipo , Humanos , Coreia (Geográfico) , Região Lombossacral , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Fragmento de Restrição , Coluna Vertebral/metabolismo , Fatores de TempoRESUMO
Osteoporosis is a disease that is strongly genetically influenced. However, the genes responsible for the disease are poorly defined. Recent data show that a G-T transition polymorphism of the Sp1 binding site at the collagen type I alpha1 gene (Sp1 polymorphism) is associated significantly with bone mineral density (BMD) and osteoporotic fracture in British women. To establish the association between the Sp1 genotypes and BMD in Korean women, we examined 200 healthy postmenopausal women of Korean ethnicity, ranging in age from 44 to 66 years (mean+/-SD: 54.7+/-5.3 years). PCR amplification using the same primers as those used previously, with enzyme digestion, revealed no restriction site in our samples. We also performed a single-strand conformational polymorphism (SSCP) analysis in 100 of the 200 samples and could not find any polymorphic sites in the PCR amplification region. Based on our study, the Sp1 polymorphism at the type I collagen alpha1 gene was not found in Korean women. Therefore, we suggest that the Sp1 polymorphism at the type I collagen alpha1 gene is absent or rare in Korean women. Based on the present findings, this polymorphism does not seem to be responsible for the entire genetic contribution to BMD.
Assuntos
Colágeno/genética , Polimorfismo Genético , Fator de Transcrição Sp1/metabolismo , Adulto , Idoso , Povo Asiático/genética , Sequência de Bases , Sítios de Ligação/genética , Densidade Óssea/genética , DNA/genética , DNA/metabolismo , Feminino , Humanos , Coreia (Geográfico) , Pessoa de Meia-Idade , Osteoporose/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita SimplesRESUMO
Interleukin-1 receptor antagonist (IL-1ra), a natural inhibitor of interleukin-1 (IL-1), completely inhibits the stimulatory effects of IL-1 on bone resorption. Bioactivity of IL-1 increases in the estrogen-deficient state with an increased IL-1:IL-1ra ratio and decreases after estrogen replacement therapy with a decreased IL-1:IL-1ra ratio. An association was found between an 86 basepair variable number tandem-repeat (VNTR) polymorphism of the IL-1ra gene and an increased production of IL-1ra in a cultured monocyte system. The IL-1ra VNTR polymorphism, therefore, is an attractive candidate gene for osteoporosis susceptibility as well as hormone responsiveness after estrogen replacement. We examined the association of this VNTR polymorphism with bone mass, bone turnover, and the change of bone mineral density (BMD) after 1 year of hormone replacement therapy (HRT). The frequencies of the five alleles were as follows: A1, 90.8% (410 bp, four repeats); A2, 7.2% (240 bp, two repeats); A3, 1.6% (500 bp, five repeats); A4, 0.4% (326 bp, three repeats); and A5, 0% (595 bp, six repeats), in 714 healthy ethnically Korean postmenopausal women, aged 41-74 years (55.2 +/- 6.3 years mean +/- SD). Spine (L2-4) and femoral neck BMD were not significantly different among IL-1ra genotypes, and no significant genotypic differences were found in bone markers. There were no differences in genotypic proportions when we categorized the subjects into a high-loss group and a normal-loss group with regard to levels of bone marker. No significant genotypic differences were found in changes in lumbar and femoral neck BMD and those in bone markers before and after 1 year of HRT in 312 women. Our data suggest that these IL-1ra polymorphisms are not associated with BMD, bone turnover, or the change of BMD after 1 year of HRT in Korean women.
Assuntos
Densidade Óssea/genética , Estrogênios/uso terapêutico , Osteoporose Pós-Menopausa/genética , Sialoglicoproteínas/genética , Adulto , Idoso , Análise de Variância , Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Estrogênios/estatística & dados numéricos , Estrogênios/farmacologia , Feminino , Colo do Fêmur/efeitos dos fármacos , Colo do Fêmur/fisiologia , Genótipo , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Coreia (Geográfico) , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/fisiologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Polimorfismo Genético/efeitos dos fármacos , Polimorfismo Genético/genética , Estatísticas não ParamétricasRESUMO
The human transforming growth factor-beta 3 (TGF-beta 3) is an important cytokine to maintain bone mass by inhibiting osteoclast differentiation. Recently raloxifene response element (RRE), a new enhancer with a polypurine sequence for estrogen receptor (ER)-mediated gene activation, was identified on the TGF-beta 3 gene. Functional analysis of the RRE-mediated pathway has shown that this would be an important pathway for bone preserving effect. We found a novel mutation in the RRE sequence by single-strand conformational polymorphism analysis in one of 200 Korean women. Cloning and sequencing revealed a heterozygote in which one allele had an insertion of 20 nucleotides (AGAGAGGGAGAGGGAGA GGG) between nucleotide +71 and +72 and a point mutation at nucleotide +75 (G-A transition), and the other allele had normal sequence. The insertion was a nearly perfect tandem duplication of the wild type DNA sequence. The bone mineral density of the affected woman was not much lower than that of age-matched controls. Transient transfection of the mutant allele showed no significantly different activity compared with that of the wild type allele. These observations suggest that the heterozygote variation of the RRE sequence seems not to be operative in determination of bone mass.