RESUMO
OBJECTIVE: Fibulin-5 is a connective tissue component and may play a role in pelvic organ prolapse (POP) pathogenesis. This study aimed to verify the association of the rs2018736 polymorphism of the fibulin-5 gene with POP in postmenopausal Brazilian women, and to determine the risk factors for POP. METHOD: This observational, cross-sectional, case-control study assessed postmenopausal women with advanced POP (stages III and IV) and control women (stages 0 and I) by examination and peripheral blood sample collection. DNA sequences were analyzed by real-time reverse-transcriptase polymerase chain reaction. A logistic regression model was used with p < 0.05 for significance. RESULTS: A total of 565 participants were evaluated (325 POP and 240 control). The homozygous C allele of rs2018736 (CC) was protective against POP (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.26-0.91). Age (OR 1.09, 95% CI 1.05-1.13), number of pregnancies (OR 1.14, 95% CI 1.01-1.28), vaginal delivery (OR 5.32, 95% CI 2.58-11.01), forceps delivery (OR 3.34, 95% CI 1.72-6.47), weight of newborn (OR 1.0007, 95% CI 1.0002-1.0011), family history of POP (OR 2.35, 95% CI 1.24-4.44), hypertension (OR 1.74, 95% CI 1.01-3.00) and diabetes (OR 2.19, 95% CI 1.07-4.48)] were independent predictors for POP; cesarean (OR 0.02, 95% CI 0.005-0.09) was protective. CONCLUSION: The rs2018736-CC genotype of the fibulin-5 gene has a protective role against POP.
Assuntos
Proteínas da Matriz Extracelular , Prolapso de Órgão Pélvico , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Humanos , Feminino , Estudos de Casos e Controles , Prolapso de Órgão Pélvico/genética , Pessoa de Meia-Idade , Proteínas da Matriz Extracelular/genética , Estudos Transversais , Pós-Menopausa/genética , Brasil , Fatores de Risco , Idoso , Predisposição Genética para Doença , GenótipoRESUMO
BACKGROUND: Postmenopausal osteoporosis is a multifactorial disease. Genetic factors play an essential role in contributing to bone mineral density (BMD) variability, which ranges from 60 to 85%. Alendronate is used as the first line of pharmacological treatment for osteoporosis; however, some patients do not respond adequately to therapy with alendronate. AIM: The aim of this work was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with response to anti-osteoporotic treatment in postmenopausal women with primary osteoporosis. METHODS: A total of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year were observed. The bone mineral density (BMD; g/cm2) of the femoral neck and lumbar spine was measured. According to BMD change, patients were divided into two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ESR1, IL-6, PTHR1, TGFß, OPG and RANKL genes were determined and profiles were generated from the combination of risk alleles. RESULTS: A total of 56 subjects were responders to alendronate and 26 subjects were non-responders. Carriers of the G-C-G-C profile (constructed from rs700518, rs1800795, rs2073618 and rs3102735) were predisposed to response to alendronate treatment (p = 0.001). CONCLUSIONS: Our findings highlight the importance of the identified profiles for the pharmacogenetics of alendronate therapy in osteoporosis.
Assuntos
Conservadores da Densidade Óssea , Osteoporose , Humanos , Feminino , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Estudos Retrospectivos , Pós-Menopausa/genética , Osteoporose/tratamento farmacológico , Vértebras LombaresRESUMO
Bone remodeling is marked by bone synthesis and absorption balance, and any altered dynamic in this process leads to osteoporosis (OP). The interaction of hormonal, environmental and genetic factors regulate bone metabolism. Since vitamin D displays a classic role in bone metabolism regulation, acting through vitamin D receptor (VDR), the genetic variants within VDR were the first ones associated with bone density and remodelling. Therefore, we investigated whether three single nucleotide polymorphisms (SNPs) within VDR were associated with OP differential susceptibility and clinical profile from postmenopausal versus healthy women from Northeast Brazil. Genetic association study enrolling 146 postmenopausal osteoporotic women as the patient group and 95 healthy age-matched women as the control group. We assessed three SNPs within VDR (rs11168268, rs1540339 and rs3890733), considering the clinical profile of all patients. Our results showed an association of rs11168268 G/G genotype with higher bone mineral density (BMD) mean for the total hip (A/A = 0.828 ± 0.09; A/G = 0.081 ± 0.13; G/G = 0.876 ± 0.12, p = .039), and the rs3890733 T/T genotype was associated with increased OP risk in patients below 60 years old (odds ratio [OR] = 5.12, 95% confidence interval [CI ]= 1.13-23.27, p = .012). The rs1540339 T/T genotype was associated with protection for individuals with low melanin deposition when compared to the high melanin deposition group (OR = 0.24, 95%CI = 0.06-0.94, p = .029). Additionally, 61% of patients presented deficient vitamin D serum levels. The SNP rs11168268 G/G was associated with a significantly increased mean total hip BMD in patients OP, highlighting this SNP and its relationship with BMD.
Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Pessoa de Meia-Idade , Densidade Óssea/genética , Genótipo , Melaninas/genética , Osteoporose/genética , Osteoporose Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Receptores de Calcitriol/genética , Vitamina DRESUMO
Postmenopausal women have more risk factors for metabolic syndrome, and genetic alterations in SLC30A8 (zinc transporter 8 [ZnT8]) are directly related to these factors. Our aim was to assess the relationship of the single nucleotide polymorphism (SNP) rs11558471 in the SLC30A8/ZnT8 gene with cardiometabolic markers in postmenopausal women. This cross-sectional study included 53 postmenopausal women divided into two groups according to the SNP genotype (AG + GG [n = 25] and AA [n = 28]). Anthropometric, dietary, and biochemical (glycemic, lipidic, hepatic, renal, and hormonal markers) variables were evaluated and compared between groups. No differences in glycemic, hepatic, renal, and hormonal markers were found between groups. However, the group with the polymorphic allele (AG + GG) had a better lipid profile than non-carriers (total cholesterol, p = 0.041; low-density lipoprotein cholesterol [LDL-c], p = 0.035; non-high-density lipoprotein cholesterol [non-HDL-c], p = 0.043). Logistic regression showed that the group with polymorphic allele had lower chances of increasing levels of LDL-c (odds ratio [OR] = 0.225, p = 0.012) and non-HDL-c (OR = 0.316, p = 0.045). After adjusting for age, body mass index, physical activity, and use of diabetes and dyslipidemia drugs, only LDL-c remained associated (OR = 0.218; p = 0.017). The variant allele of SNP rs11558471 in the SLC30A8 gene was associated with better LDL-c levels, which helps reduce the risks for cardiovascular diseases in postmenopausal women.
Assuntos
Doenças Cardiovasculares , Pós-Menopausa , Humanos , Feminino , Transportador 8 de Zinco/genética , LDL-Colesterol , Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Transversais , Colesterol , Genótipo , Doenças Cardiovasculares/genéticaRESUMO
OBJECTIVE: This study aimed to verify the presence of polymorphism rs2165241 of the lysyl oxidase-like 1 (Loxl1) gene and its association with pelvic organ prolapse (POP) in Brazilian women and determine risk factors for POP development. METHODS: The study was previously approved by the local research and ethics board. Postmenopausal women were included and divided into POP (stages III and IV) and control (stages 0 and I) groups. Peripheral blood samples were collected, and the DNA sequence of interest was analyzed by real-time reverse-transcriptase polymerase chain reaction. We used logistic regression and considered a recessive model of inheritance for the analysis, with p < 0.05 for significance. RESULTS: A total of 836 women were assessed: 426 POP cases and 410 controls. The frequencies of CC, CT and TT genotypes were similar in both groups. Age (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.07; 1.14), number of vaginal births (OR = 17.06, 95% CI = 5.94; 48.97), family history (OR = 2.87, 95% CI = 1.57; 5.22) and weight of largest newborn (OR = 1.001, 95% CI = 1.0003; 1.001) were independent risk factors for POP, while multiple cesarean sections (two or more) was protective (OR = 0.17, 95% CI = 0.07; 0.42). CONCLUSION: No association was detected between rs2165241 of the Loxl1 gene and POP.
Assuntos
Prolapso de Órgão Pélvico , Pós-Menopausa , Aminoácido Oxirredutases/genética , Feminino , Humanos , Recém-Nascido , Prolapso de Órgão Pélvico/genética , Polimorfismo Genético , Pós-Menopausa/genética , Gravidez , VaginaRESUMO
Background: The Wnt/ß catenin pathway promotes bone mineralization stimulating proliferation, differentiation, and survival of osteoblasts; it also inhibits osteoclast differentiation and osteocyte activity. Sclerostin (SOST) and Dickkopf 1 (DKK1) are Wnt/ß catenin pathway inhibitors. Genetic variability in the expression of SOST and DKK1 might be involved in the development of postmenopausal osteoporosis (OP). Aim: To determine whether the SOST rs851056 and DKK1 rs1569198 polymorphisms are associated with OP in Mexican-Mestizo postmenopausal women. Materials and Methods: Two hundred and eighty Mexican-Mestizo postmenopausal women were assessed for their bone mineral density by dual-energy X-ray absorptiometry (DXA). Patients were classified as OP or non-OP. Genomic DNA was extracted from peripheral blood leukocytes. Genetic polymorphisms were analyzed by quantitative polymerase chain reaction using TaqMan probes. Results: The frequency of OP was 40% among the study population. Osteoporotic patients were older (p < 0.001), had a higher frequency of smoking (p = 0.01), and lower body mass index (p < 0.001) compared with the non-osteoporotic patients. The genotypic frequencies of the rs851056 locus of the SOST gene were GG 19%, GC 45%, and CC 35%, whereas the genotypic frequencies of the rs1569198 locus of the DKK1 gene were GG 15%, GA 40%, and AA 44%. In relation to rs851056 locus of the SOST gene, no differences were observed between the OP and non-OP cohorts in the frequencies of the GC polymorphism (48.7% vs. 43.1%). Similarly, analyses of the DKK1 rs1569198 does not demonstrate differences in the GA genotypic frequencies between the OP and non-OP cohorts (42.5% vs. 38.9%). Conclusion: Polymorphisms SOST rs851056 and DKK1 rs1569198 polymorphisms are not associated with OP in Mexican-Mestizo postmenopausal women.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteoporose Pós-Menopausa/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Densidade Óssea/genética , Estudos de Casos e Controles , Etnicidade/genética , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , México/epidemiologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Pós-Menopausa/genética , Via de Sinalização Wnt/genéticaRESUMO
PURPOSE: Vitamin D deficiency (VDD) and polymorphisms in the group-specific component (GC) gene are known to be associated in different populations. However, the effects of such genetic variants may vary across different populations. Thus, the objective of this study was to estimate the association between Vitamin D-Binding Protein (VDBP) haplotypes and VDD in mestizo postmenopausal women and Mexican Amerindian ethnic groups. METHODS: This was a cross-sectional study of 726 postmenopausal Mexican women from the Health Workers Cohort Study (HWCS) and 166 postmenopausal women from the Metabolic Analysis in an Indigenous Sample (MAIS) cohort in Mexico. GC polymorphisms (rs7045 and rs4588) were analyzed by TaqMan probes. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured by Chemiluminescent Microparticle Immuno Assay. RESULTS: The prevalence of VDD serum 25(OH)D < 20 ng/mL was 43.7% in mestizo women and 44.6% in indigenous women. In HWCS, the single nucleotide polymorphisms (SNPs) rs7041 and rs4588 were associated with VDD. In addition, women from the HWCS, carrying the haplotypes GC2/2 and GC1f/2 had higher odds of VDD (OR = 2.83, 95% CI 1.14, 7.02; and OR = 2.30, 95% CI 1.40, 3.78, respectively) compared to women with haplotype 1f/1 s. These associations were not statistically significant in the MAIS cohort. CONCLUSIONS: Our results show genetic association of the analyzed SNPs and related haplotypes, on the GC gene, with VDD in mestizo Mexican postmenopausal women. Moreover, a high prevalence of VDD with high genetic variability within the country was observed. Our results support the need for national policies for preventing VDD.
Assuntos
Pós-Menopausa , Deficiência de Vitamina D/etnologia , Deficiência de Vitamina D/genética , Proteína de Ligação a Vitamina D/genética , Idoso , Alelos , Estudos de Coortes , Estudos Transversais , Etnicidade/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/etnologia , Grupos Populacionais/genética , Pós-Menopausa/sangue , Pós-Menopausa/etnologia , Pós-Menopausa/genética , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
Objective: The aim of this study was to analyze the genetic association of five ESR1 single nucleotide polymorphisms (SNPs) (rs3020331, rs851982, rs1999805, rs2234693, rs3020404), four COL1A1 SNPs (rs1800012, rs2075555, rs2412298, rs1107946), and two SNPs on the CCDC170 gene (rs9479055, rs4870044) with distal radius fracture (DRF) in a group of postmenopausal Mexican women.Methods: A case-control study was conducted. Cases (n = 182) were women above the age of 38 years with low-energy DRF, and controls (n = 201) were women without. Analysis was done through real-time polymerase chain reaction. Frequencies and Hardy-Weinberg equilibrium were calculated. A multivariate analysis including bone mass index, age, menarche, and menopause as covariables was carried out. Finally, haplotype and linkage disequilibrium (LD) analyses were performed.Results:COL1A1 rs1107946 was strongly associated with DRF. Both CCDC170 SNPs showed strong association with DRF. For the ESR1 gene, four SNPs (rs2234693, 3020404, rs3020331, and rs851982) showed very strong association with DRF. Additionally, the region between the latter two showed strong LD.Conclusions: A strong association of DRF with variants in these genes was found, including haplotypes and a region with strong LD on ESR1. The results suggest that these SNPs could be useful to detect the population at risk of presenting DRF among Mexican perimenopausal women.
Assuntos
Proteínas de Transporte/genética , Colágeno Tipo I/genética , Receptor alfa de Estrogênio/genética , Pós-Menopausa/genética , Fraturas do Rádio/genética , Idoso , Estudos de Casos e Controles , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Humanos , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Osteoporosis is a metabolic bone disorder characterized by low bone mineral density and decreased bone strength, leading to an increased risk of fractures with a consequent increase in morbidity and mortality. The current methods to estimate the fracture risk are very limited. microRNAs (miRNAs) have been considered as good biomarkers for many pathological processes, including osteoporosis. Some circulating miRNAs are associated with regulation of bone formation and differentiation of bone cells. The aim of this study, was to analyze the expression of miRNAs in serum of patients with osteoporosis (nâ¯=â¯20) and healthy controls (nâ¯=â¯20). Expression of 754 miRNAs was analyzed through quantitative real time RT-PCR arrays. Seven miRNAs showed significant differences between groups. The microRNAs miR-23b-3p, miR-140-3p and miR-885-5p were selected based on fold change and p-values (40.5, pâ¯=â¯0.038, 20.7, pâ¯=â¯0.045, and 2.2, pâ¯=â¯0.002; respectively) for validation in independent serum samples from patients with osteopenia (nâ¯=â¯28), osteoporosis (nâ¯=â¯26) and osteoporotic hip fracture (nâ¯=â¯21). After validation, we confirm differences across the groups for miR-23b-3p and miR-140-3p. Our data pointed miR-140-3p and miR-23b-3p as potential biomarkers candidates for osteoporosis in postmenopausal women.
Assuntos
MicroRNAs/sangue , Osteoporose/genética , Fraturas por Osteoporose/genética , Pós-Menopausa/genética , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , México , Osteoporose/sangue , Osteoporose/complicações , Fraturas por Osteoporose/sangue , Pós-Menopausa/sangueRESUMO
Genome-wide association studies in people with European ancestry suggest that polymorphisms in genes involved in vitamin D (VD) metabolism have an effect on serum concentrations of 25-hydroxyvitamin D. However, nothing is known about these polymorphisms in populations with Amerindian ancestry. Our aim was to evaluate the association between genetic variants on the vitamin D receptor (VDR) and the vitamin D binding protein (GC) genes, involved in the VD pathway, and VD deficiency in 689 unrelated Mexican postmenopausal women. We also described the frequencies of these variants in 355 postmenopausal women from different ethnic groups. Based on our preliminary results of 400 unrelated Mexican postmenopausal women, three single nucleotide polymorphisms (SNPs) were selected for genotyping. The SNPs rs4516035 in VDR and rs2282679 in GC were associated with VD deficiency. Additionally, women who carried three risk alleles had a 3.67 times higher risk of suffering VD deficiency, compared to women with no risk alleles (p = 0.002). The rs4516035-C allele frequency in the Amerindian population was enriched in the South East region of Mexico. In contrast, the highest frequency of the rs2298850-C allele, a proxy for the tag SNP rs2282679, was observed in the South region. Our results indicate that genetic variants in VDR and GC genes are associated with VD deficiency in Mexican postmenopausal women. Moreover, an association was observed for the variants rs3794060 and rs4944957 of the DHCR7/NADSYN1 gene with osteopenia/osteoporosis.