The rs2018736 fibulin-5 polymorphism as a determinant for pelvic organ prolapse: a case-control study.

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.

Vitamin D receptor gene polymorphisms influence on clinical profile and bone mineral density at different skeletal sites in postmenopausal osteoporotic women.

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.

Influence of the Osteogenomic Profile in Response to Alendronate Therapy in Postmenopausal Women with Osteoporosis: A Retrospective Cohort Study.

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.

Relationship Between the Single Nucleotide Polymorphism rs11558471 in the SLC30A8/ZnT8 Gene and Cardiometabolic Markers in Postmenopausal Women.

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.

The rs2165241 polymorphism of the Loxl1 gene in postmenopausal women with pelvic organ prolapse.

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.

Genotypic Analyses of the Sclerostin rs851056 and Dickkopf rs1569198 Polymorphisms in Mexican-Mestizo Postmenopausal Osteoporosis: A Case-Control Study.

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.

Association between vitamin D deficiency and common variants of Vitamin D binding protein gene among Mexican Mestizo and indigenous postmenopausal women.

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.

COL1A1, CCDC170, and ESR1 single nucleotide polymorphisms associated with distal radius fracture in postmenopausal Mexican women.

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.

Serum miRNAs miR-140-3p and miR-23b-3p as potential biomarkers for osteoporosis and osteoporotic fracture in postmenopausal Mexican-Mestizo women.

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 (n = 20) and healthy controls (n = 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, p = 0.038, 20.7, p = 0.045, and 2.2, p = 0.002; respectively) for validation in independent serum samples from patients with osteopenia (n = 28), osteoporosis (n = 26) and osteoporotic hip fracture (n = 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.

Association between Vitamin D Deficiency and Single Nucleotide Polymorphisms in the Vitamin D Receptor and GC Genes and Analysis of Their Distribution in Mexican Postmenopausal Women.

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.

Association of PvuII and XbaI polymorphisms on estrogen receptor alpha (ESR1) gene to changes into serum lipid profile of post-menopausal women: Effects of aging, body mass index and breast cancer incidence.

Estrogen is a steroidal hormone involved in several physiological functions in the female body including regulation of serum lipid metabolism and breast cancer (BC). Estrogen actions on serum lipids mostly occur through its binding to intracellular Estrogen Receptor alpha (ERalpha) isoform, expressed in most of tissues. This gene (ESR1) exhibit many polymorphic sites (SNPs) located either on translated and non-translated regions that regulate ERalpha protein expression and function. This paper aimed to investigate the association of two intronic SNPs of ESR1 gene, namely c454-397T>C (PvuII) and c454-351A>G (XbaI) to alterations in serum levels of total cholesterol (T-chol), total lipid (TL), low density lipoprotein cholesterol (LDL), high density lipoprotein (HDL), and triglycerides (TG) in a cohort of post-menopausal women. In addition, we aimed to associate presence of these SNPs to development of BC along 5 years period. To do so, a group of healthy 499, highly miscigenated, post-menopausal Brazilian women, were carried using PCR-FRLP technique and further confirmed by automatic sequence analysis as well followed through 5 years for BC incidence. Measurements of serum lipid profile by standard commercial methods were carried individually whereas Dual Energy X-ray Absorciometry (DXA) measured Body Mass Indexes (BMI), Fat Mass (FM), Lean Body Mass (LBM), and Body Water Content (BWC). No effects of PvuII SNP on ESR1 gene were observed on patient´s serum T-chol, TL, LDL, HDL, and TG. However, c454-397T>C PvuII SNP is associated to lower body fat and higher levels of lean mass and body water and lower incidence of BC. On the other hand, statistically significant effect of XbaI c454-351A>G SNP on serum TG and TL levels. Patients homozygous for X allele were followed up from 2010-2015. They showed higher incidence of breast cancer (BC) when compared to either heterozygous and any P allele combination. Moreover, the increasing of TG and TL serum concentrations associated to SNP XbaI c454-351A>G on ESR1 gene is enhanced in both obese (higher BMI) and elder women. Taken together, these results suggested that XbaI c454-351A>G SNP is associated to changes in lipid profile, particularly in serum TG and TL, in this cohort of post-menopausal woman. Also, this paper shows another link between obesity and BC corroborating the current thesis that both diseases are interlinked.

Polymorphisms in key bone modulator cytokines genes influence bisphosphonates therapy in postmenopausal women.

Osteoporosis is a multifactorial and debilitating disease resulting from decreased bone mineral density (BMD) and loss of tissue microarchitecture. Ineffective therapies may lead to bone fractures and subsequent death. Single nucleotide polymorphisms (SNPs) in key immune regulator genes have been associated with therapeutic response to bisphosphonates, which are the first therapeutic line of choice for osteoporosis. However, cytokine pathways and their relation with therapeutic adhesion remain to be fully elucidated. Aimed at better understanding these processes, we investigated the response to bisphosphonate therapy in postmenopausal women and four SNPs in key proinflammatory cytokines genes: IL23R +2284 (C>A) (rs10889677), IL17A +672 (G>A) (rs7747909), IL12B +1188 (T>G) (rs3212227) and INF-γ -1616 (G>A) (rs2069705). A total of 69 patients treated with bisphosphonate were followed for a period of 1 up to 4 years, genotyped and compared according to their changes in bone mineral density (BMD) and level of biochemical markers during their treatment. The INF-γ -1616 G/G associated with increased BMD values in femoral neck (GG/AA, p = 0.016) and decreased BMD values in total hip (GG/GA, p = 0.019; GG/AA, p = 0.011). In relation to biochemical markers, INF-γ -1616 SNP associated with increased alkaline phosphatase (GG/AA; p < 0.0001) and parathyroid hormone levels (AA/GA; p = 0.017). Vitamin D values changes were related to IL17A +672 (GG/GA, p = 0.034) and to IL12B +1188 (TT/TG, p = 0.046) SNPs. Besides, significant differences in changes of calcium levels correlated with IL23R +2284 (CC/CA, p = 0.016) genotypes. Altogether, we suggest that these polymorphisms may play an important role for therapeutic decisions in osteoporosis treatment.

Association between global leukocyte DNA methylation and cardiovascular risk in postmenopausal women.

BACKGROUND: Genetic studies to date have not provided satisfactory evidence regarding risk polymorphisms for cardiovascular disease (CVD). Conversely, epigenetic mechanisms, including DNA methylation, seem to influence the risk of CVD and related conditions. Because postmenopausal women experience an increase in CVD, we set out to determine whether global DNA methylation was associated with cardiovascular risk in this population. METHODS: In this cross sectional study carried out in a university hospital, 90 postmenopausal women without prior CVD diagnosis (55.5 ± 4.9 years, 5.8 [3.0-10.0] years since menopause) were enrolled. DNA was extracted from peripheral leukocytes and global DNA methylation levels were obtained with an ELISA kit. Cardiovascular risk was estimated by the Framingham General Cardiovascular Risk Score (10-year risk) (FRS). Clinical and laboratory variables were assessed. Patients were stratified into two CVD risk groups: low (FRS: <10 %, n = 69) and intermediate/high risk (FRS ≥10 %, n = 21). RESULTS: Age, time since menopause, blood pressure, total cholesterol, and LDL-c levels were higher in FRS ≥10 % group vs. FRS <10 % group. BMI, triglycerides, HDL-c, HOMA-IR, glucose and hsC-reactive protein levels were similar in the two groups. Global DNA methylation (% 5mC) in the overall sample was 26.5 % (23.6-36.9). The FRS ≥10 % group presented lower global methylation levels compared with the FRS <10 % group: 23.9 % (20.6-29.1) vs. 28.8 % (24.3-39.6), p = 0.02. This analysis remained significant even after adjustment for time since menopause (p = 0.02). CONCLUSIONS: Our results indicate that lower global DNA methylation is associated with higher cardiovascular risk in postmenopausal women.

Increased mood symptoms in postmenopausal women related to the polymorphism rs743572 of the CYP17 A1 gene.

BACKGROUND: Menopausal and depressive symptoms are highly prevalent after the menopause; but may vary from one population to another and genetics play a key role. OBJECTIVE: To analyze the intensity of these symptoms in relation to the genetic variants of the rs743572 polymorphism of the CYP17 A1 gene in postmenopausal women. METHODS: DNA was extracted from the whole blood of 168 natural postmenopausal women (40-65 years) and tested for the rs743572 polymorphism of the CYP17 A1 gene. Intensity of menopausal (Menopause Rating Scale, MRS) and depressive symptoms (Hospital Anxiety and Depressive Scale, HADS) were correlated to polymorphism genotypes. RESULTS: Women with the GG genotype of the rs743572 polymorphism displayed significantly higher scores for the MRS (items 5 and 6 [irritability and anxiety] and the psychological subscale) and the HADS (total and subscales). CONCLUSION: The intensity of menopausal symptoms related to mood was found higher among postmenopausal women presenting the GG genotype of the rs743572 polymorphism of the CYP17 A1 gene. There is a need for more research in this regard.

Association of the IGF-1 rs35767 and rs972936 polymorphisms with the risk of osteoporosis in a Chinese postmenopausal female population.

The aim of our study was to conduct a case-control study in a Chinese postmenopausal population to evaluate the roles of the IGF-1 rs35767 and rs972936 polymorphisms on bone mineral density (BMD) levels and osteoporosis risk. A total of 272 consecutive postmenopausal women with a primary diagnosis of osteoporosis and 272 controls were enrolled in the study between 2012 and 2014. The polymerase chain reaction-restriction fragment length polymorphism method was used to genotype the rs35767 and rs972936 IGF-1 polymorphisms. By comparing the demographic characteristics between patients and controls, patients with osteoporosis were found to be more likely to have a habit of alcohol drinking (P = 0.023). Furthermore, the BMD levels of the L1-L4 vertebrae, femoral necks, total hips, and trochanters in patients with osteoporosis were significantly lower than those in controls. By conditional regression analysis, we found that the IGF-1 rs2288377 and rs972936 gene polymorphisms were not associated with the risk of osteoporosis (P < 0.05). However, the CT+TT genotype of rs35767 and the AG+GG genotype of rs972936 were significantly associated with lower BMD levels in the femoral neck. Overall, our study suggests that IGF-1 rs2288377 and rs972936 gene polymorphisms do not influence the risk osteoporosis.

HLA-A gene polymorphisms contribute to osteoporosis susceptibility in postmenopausal Han Chinese women.

Osteoporosis is a common disease characterized by low bone mineral density, deterioration in bone microarchitecture, and increased fracture risk and is more prevalent in postmenopausal women. HLA is a complex gene family; previous studies have shown that it plays an important role in the pathogenesis of osteoporosis among Japanese and Greek populations. Prompted by these findings, this study was designed to explore the associations between HLA-A gene polymorphisms and postmenopausal osteoporosis in the Han Chinese population. The polymerase chain reaction-sequence-based typing method was used for DNA genotyping at the HLA-A locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls. We identified 17 HLA-A alleles in patients with postmenopausal osteoporosis and 20 HLA-A alleles in control subjects. Furthermore, we found that the frequency of the HLA-A* 02:07 allele was significantly higher in patients with postmenopausal osteoporosis than in control subjects (P = 0.023), and the relative risk was 4.065 (95% confidence interval = 1.109-14.893). Our study provides supportive evidence for the contribution of HLA-A gene polymorphisms to the susceptibility to postmenopausal osteoporosis and suggests that HLA-A* 02:07 is likely an important genetic risk factor for postmenopausal osteoporosis in the Han Chinese population.

Association between polymorphisms in the thymidylate synthase gene and risk of breast cancer in a Mexican population.

Breast cancer (BC) is the leading cause of cancer-related deaths among women in Mexico. Two single-nucleotide polymorphisms (SNPs) in the thymidylate synthase (TS) gene, the 28-base pair (bp) tandem repeat in the TS 5'-untranslated enhanced region (TSER) and the 6-bp insertion/deletion in the TS 3'-untranslated region (TS 3'-UTR), increase the rate of misincorporation of uridylate into DNA and may lead to chromosomal damage. We examined the association between these polymorphisms and BC risk in Mexican women according to menopause status. Mexican patients with initial BC diagnosis (N = 230) and 145 individuals from a reference general population group (RGP) were included. For statistical analysis, the BC group was divided into pre- and post-menopause groups (PRE and POST groups, respectively). We analyzed both TS polymorphisms (TSER and TS 3'-UTR) using polymerase chain reaction. Finetti analysis was used to evaluate inter-and intra-group differences. The results showed a high frequency for the 3R and ins6 alleles in the BC, RGP, PRE, and POST groups. No significant differences were observed for the TS and TSER genotype and allele frequency distributions between groups. We found that the TSER and TS 3'-UTR SNPs are not associated with BC risk in Mexican patients.

Analysis of association of MEF2C, SOST and JAG1 genes with bone mineral density in Mexican-Mestizo postmenopausal women.

BACKGROUND: Osteoporosis, a disease characterized by low bone mineral density (BMD), is an important health problem in Mexico. BMD is a highly heritable trait, with heritability estimates of 50-85%. Several candidate genes have been evaluated to identify those involved in BMD variation and the etiology of osteoporosis. This study investigated the possible association of single-nucleotide polymorphisms (SNPs) in the MEF2C, SOST and JAG1genes with bone mineral density (BMD) variation in postmenopausal Mexican-Mestizo women. METHODS: Four hundred unrelated postmenopausal women were included in the study. Risk factors were recorded and BMD was measured in total hip, femoral neck and lumbar spine using dual-energy X-ray absorptiometry. In an initial stage, a total of twenty-five SNPs within or near SOST gene and seven SNPs in the JAG1 gene were genotyped using a GoldenGate assay. In a second stage, three MEF2C gene SNPs were also genotyped and SOST and JAG1 gene variants were validated. Real time PCR and TaqMan probes were used for genotyping. RESULTS: Linear regression analyses adjusted by age, body mass index and ancestry estimates, showed that five SNPs in the SOST gene were significantly associated with BMD in total hip and femoral neck but not lumbar spine. The lowest p value was 0.0012, well below the multiple-test significance threshold (p=0.009), with mean effect size of -0.027 SD per risk allele. We did not find significant associations between BMD and MEF2C/JAG1 gene variants [rs1366594 "A" allele: ß=0.001 (95% CI -0.016; 0.017), P=0.938; rs2273061 "G" allele: ß=0.007 (95% CI -0.007; 0.023), p=0.409]. CONCLUSIONS: SOST polymorphisms may contribute to total hip and femoral neck BMD variation in Mexican postmenopausal women. Together, these and prior findings suggest that this gene may contribute to BMD variation across populations of diverse ancestry.

Relation of the estrogen receptor and vitamin D receptor polymorphisms with bone mineral density in postmenopausal Mexican-mestizo women.

BACKGROUND: Since osteoporosis is a complex disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors, the aim of this study was to analyze the possible association among one polymorphism of VDR and two polymorphisms of ESR1; as well as their haplotypes with BMD in postmenopausal Mexican-mestizo women. METHODS: We studied 742 postmenopausal Mexican-mestizo women. A structured questionnaire for risk factors was applied and BMD was measured in the lumbar spine and total hip by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. One polymorphism of VDR (rs11568820) and two of ESR1 (rs2234693 and rs9340799) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Hardy-Weinberg equilibrium was tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2); haplotype analysis was conducted. RESULTS: Rs9340799 of ESR1 and one haplotype formed by the two polymorphisms of the ESR1 were significantly associated with FN-BMD variations. Moreover, analysis of the genotype of rs11568820 of VDR and the rs2234693 of ESR1 showed no significant differences with BMD variations. CONCLUSIONS: Our results showed that rs9340799 and one haplotype of ESR1 were significantly associated with BMD only at the femoral neck and this association remained after adjusting for covariates.

Frequencies of interleukin-6, GST and progesterone receptor gene polymorphisms in postmenopausal women with low bone mineral density.

CONTEXT AND OBJECTIVE: Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD). Studies have shown that some of the genetic components relating to lower BMD may be detected by polymorphisms. Our aim was to evaluate the frequencies of interleukin-6, GST and progesterone receptor gene polymorphisms in postmenopausal women with low BMD. DESIGN AND SETTING: Cross-sectional study, conducted in a public university in São Paulo, Brazil. METHODS: We evaluated interleukin-6 (IL-6), progesterone receptor gene (PROGINS) and glutathione S-transferase (GST) polymorphisms in 110 postmenopausal women with no previous use of hormone therapy. Tests were performed using DNA-PCR, from oral scrapings. We used Student's t-test and a logistic regression model for statistical analysis. RESULTS: Regarding IL-6 polymorphism, 58.2% of the patients were homozygotes (GG) and 41.8% had allele C (heterozygote or mutant homozygote + GC or CC). PROGINS genotype polymorphism was absent in 79% (wild homozygote or P1/P1) and present in 20.9% (heterozygote or P1/P2). Regarding GSTM1 polymorphism, the allele (1/1) was present in 72.7% of the patients and was absent in 27.3%. We found that IL-6 polymorphism had statistically significant correlations with the L2-L4 T-score (P = 0.032) and with BMD (P = 0.005). Women with IL-6 polymorphism were 2.3 times more likely to have a L2-L4 T-score of less than -1, compared with those not presenting this polymorphism. CONCLUSION: IL-6 gene polymorphism was correlated with low BMD, whereas the PROGINS and GSTM1 polymorphisms did not show any correlation.