Apa-I polymorphism in VDR gene is related to metabolic syndrome in polycystic ovary syndrome: a cross-sectional study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder determined by polygenic traits as well as environmental factors. Lower vitamin D levels have been detected in PCOS women and related to hormone and metabolic disturbances. Vitamin D acts in tissues through the vitamin D receptor (VDR). VDR gene variants have been associated with worse metabolic profile in the general population. We investigated the genotype and haplotype distribution of the Bsm-I (rs1544410), Apa-I (rs7975232), and Taq-I (rs731236) VDR gene polymorphisms in PCOS and non-hirsute women from southern Brazil. We further investigated the associations of these gene variants and their haplotypes with PCOS, vitamin D levels, and metabolic abnormalities, including the metabolic syndrome (MetS). METHODS: A group of 191 women with PCOS (Rotterdam criteria) and 100 non-hirsute controls with regular ovulatory cycles were genotyped for all polymorphisms by real-time PCR, with allelic discrimination assays. MetS and the cutoffs for its isolated components were defined in accordance with the Joint Scientific Statement. RESULTS: Women with PCOS were younger and had significantly higher BMI and total testosterone levels than controls (p < 0.05). The frequency of MetS in PCOS and controls was 26.5% and 4.8% respectively. The CC genotype of Apa-I entailed higher risk of MetS in PCOS (OR: 2.133; 95% CI 1.020-4.464, p = 0.042), and was associated with higher systolic blood pressure (p = 0.009), total cholesterol (p = 0.040), and LDL-cholesterol (p = 0.038) in both PCOS and control groups (two-way ANOVA). The frequencies of VDR haplotypes were similar in PCOS and control women. CONCLUSIONS: The present results suggest that the Apa-I variant in VDR gene may be associated with MetS in southern Brazilian women with PCOS, and with blood pressure, total cholesterol, and LDL-c in women with and without PCOS.

Salivary Cortisol, Perceived Stress, and Metabolic Syndrome: A Matched Case-Control Study in Female Shift Workers.

Although the pathogenesis of metabolic syndrome (MetS) is complex and multifactorial, there is limited information if psychological factors, such as stress exposure, are involved in the etiology of MetS. Therefore, this study investigated the associations between MetS and cortisol levels and perceived stress levels among women shift workers in Southern Brazil. A matched case-control study was conducted, including 50 cases of MetS and 200 age-matched controls (±3 years, 4 for each case). Salivary cortisol levels were evaluated immediately after waking and one upon returning home from work. Perceived stress levels were measured by the Perceived Stress Scale with 10 items (PSS-10). Multivariate-adjusted associations between MetS and salivary cortisol levels and perceived stress levels were assessed by conditional logistic regression. Means±standard deviations of salivary cortisol levels were not significantly different between cases and controls either immediately after waking (5.37±4.10 vs. 6.03±5.39 nmol/l; p = 0.53) or after work (2.74±2.87 vs. 2.78±2.85 nmol/l; p = 0.93). There was no significant difference in perceived stress level between cases and controls (14.2±5.9 vs. 15.5±5.6; p = 0.15). No independent association was observed in the multivariate model between MetS and salivary cortisol level or perceived stress level after these exposures were stratified into tertiles. Overall, there was no difference between women with or without MetS in regard to the free salivary cortisol and perceived stress. Our results do not support an association between stress exposure and MetS among women shift workers.

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.

Genetic variant in vitamin D-binding protein is associated with metabolic syndrome and lower 25-hydroxyvitamin D levels in polycystic ovary syndrome: A cross-sectional study.

Vitamin D deficiency has been related to metabolic syndrome (MetS) in polycystic ovary syndrome (PCOS). The vitamin D-binding protein (DBP) is the main protein involved in vitamin D transport. Two single-nucleotide polymorphisms (SNPs) of the DBP gene, rs4588 and rs7041, have been associated with low circulating levels of 25-hydroxyvitamin D [25(OH)D] in various populations, but not in women with PCOS. Therefore, we determined the genotype and haplotype distribution of DBP gene polymorphisms and investigated the associations between these genetic variants and their haplotypes with PCOS, MetS, and 25(OH)D levels in women with PCOS and controls from the South of Brazil. The sample included 291 women (191 with PCOS and 100 controls). All participants were genotyped for polymorphisms rs2282679, rs4588, and rs7041. Serum 25(OH)D levels were determined in a subset of 102 participants. Women with PCOS were younger and had significantly higher body mass index, blood pressure, and insulin resistance than the control group (p<0.05). The prevalence of MetS in PCOS and controls was 26.5% and 4.8% respectively. Levels of 25(OH)D were lower in PCOS women with MetS, even after adjustment for age (p = 0.033). No associations were observed between PCOS and the polymorphisms or their haplotypes. A higher frequency of genotype TT of rs7041 was found in PCOS participants with MetS (OR: 2.21, 95%CI:1.08-4.52; p = 0.027). This same genotype was associated with lower 25(OH)D levels in both PCOS and control women (OR: 4.40, 95%CI:1.62-12.00; p = 0.002). In conclusion, these findings indicate that DBP gene polymorphisms and their haplotypes are not directly associated with PCOS. In contrast, the TT genotype of SNP rs7041 was associated with MetS in PCOS women, and with lower 25(OH)D levels in both PCOS and control groups.

Blood Trace Element Concentrations in Polycystic Ovary Syndrome: Systematic Review and Meta-analysis.

Polycystic ovary syndrome (PCOS) is a prevalent condition in women of reproductive age. PCOS is characterized by androgen excess and chronic anovulation and associated with low-grade inflammation and metabolic comorbidities. Some trace elements have been linked to pathophysiological mechanisms of oxidative stress and inflammation in different disorders. Therefore, we conducted a systematic review and meta-analysis of the available evidence regarding trace element concentrations in PCOS. We reviewed MEDLINE and EMBASE in search of case-control, cross-sectional, and cohort studies published until September 2015. Of 183 studies identified, six were selected for systematic review. All used the Rotterdam criteria for the diagnosis of PCOS. Two studies evaluating chromium and one assessing cobalt levels did not observe differences between PCOS and controls. Another study recorded similar nickel and vanadium levels between the groups, but lower selenium concentrations in women with PCOS compared to controls. Four studies were included in the random effects model meta-analysis, for a total of 264 PCOS and 151 control women. Copper levels were found to be higher in women with PCOS than in controls [mean difference 0.12 ppm (95 % CI 0.07; 0.17 ppm); I 2 = 0 %]. Manganese [mean difference 0.04 ppm (95 % CI -0.05; 0.13 ppm); I 2 = 94.4 %] and zinc concentrations [mean difference 0.02 ppm (95 % CI -0.12; 0.16 ppm); I 2 = 92.4 %] were similar between the groups. The present results suggest a relationship between increased copper concentration and PCOS. This systematic review and meta-analysis is registered in PROSPERO under number CRD42016034036.

Circulating and peritoneal fluid interleukin-6 levels and gene expression in pelvic endometriosis.

Current data are inconsistent regarding the association between interleukin-6 (IL-6), a marker of acute phase inflammation, and pelvic endometriosis. The aim of the present study was to assess IL-6 levels in serum and peritoneal fluid (PF), as well as IL-6 gene expression in adipose tissue (AT) and endometrial samples in pelvic endometriosis. A total of 30 patients with endometriosis and 18 women with a normal pelvis were enrolled in this case-control study. IL-6 levels in PF and serum were determined using a human enzyme-linked immunosorbent assay and IL-6 gene expression was evaluated using reverse transcription-quantitative polymerase chain reaction. It was observed that IL-6 levels in the PF were higher in patients with endometriosis than in the control group (P=0.047) and patients with stage III/IV endometriosis exhibited higher IL-6 levels in the PF than those with stage I/II endometriosis and the control group (P<0.001). Furthermore, a strong correlation between PF IL-6 levels and the revised American Society for Reproductive Medicine score for endometriosis severity was identified (r=0.77; P<0.001). IL-6 gene expression did not differ significantly between endometriosis and control groups in endometrial samples or in AT of both groups. The results of the current study suggest that there may be an association between IL-6 and the presence and severity of pelvic endometriosis. The source of this higher IL-6 seems not to be specifically related to regional AT.

Gene expression of leptin and long leptin receptor isoform in endometriosis: a case-control study.

In this study, leptin/BMI ratio in serum and peritoneal fluid and gene expression of leptin and long form leptin receptor (OB-RL) were assessed in eutopic and ectopic endometria of women with endometriosis and controls. Increased serum leptin/BMI ratio was found in endometriosis patients. Leptin and OB-RL gene expression was significantly higher in ectopic versus eutopic endometrium of patients and controls. A positive, significant correlation was observed between leptin and OB-RL transcripts in ectopic endometria and also in eutopic endometria in endometriosis and control groups. A negative and significant correlation was found between OB-RL mRNA expression and peritoneal fluid leptin/BMI ratio only in endometriosis. These data suggest that, through a modulatory interaction with its active receptor, leptin might play a role in the development of endometrial implants.

Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome.

OBJECTIVE: To determine leptin and adiponectin serum levels and gene expression in subcutaneous adipose tissue from women with polycystic ovary syndrome (PCOS) and nonhirsute, ovulatory women; and leptin/adiponectin (L/A) ratio. DESIGN: Case-control study. SETTING: University hospital gynecologic endocrinology unit. PATIENT(S): Thirty-one women with PCOS and 57 controls. INTERVENTION(S): Anthropometric, hormonal, and metabolic assessment; subcutaneous adipose tissue biopsy. MAIN OUTCOME MEASURE(S): Leptin and adiponectin serum levels, L/A ratio, controlled by age, and gene expression in women with PCOS and controls, stratified by body mass index and variables associated with androgen excess and insulin resistance. RESULT(S): Serum leptin was higher in overweight/obese patients with PCOS than in all normal-weight control women. Adiponectin levels were similar in all subgroups. The L/A ratio was lower in normal-weight controls (1.80; range 0.94-3.72) than in overweight/obese controls (5.27; range 2.66-13.58) and patients with PCOS (7.73; range 3.81-15.04). Subcutaneous leptin messenger RNA was higher in overweight/obese women with PCOS than in normal-weight controls (2.316 [range 1.987-2.580] vs. 1.687 [range 1.518-2.212]). Adiponectin gene expression was similar in all groups. Positive correlations were found between serum and messenger RNA levels for both leptin and adiponectin. On multiple regression analysis, percentage of body fat contributed significantly to L/A ratio in PCOS, independently of body mass index and free androgen index. CONCLUSION(S): In PCOS, altered adipocyte secretion seems to relate to adiposity rather than to androgen excess.

Perfil lipídico de transplantados renais em uso de terapia imunossupressora / Lipid profile in post renal transplant patients treated with immunosuppressive therapy

Objetivo: A prevalência de alterações no perfil lipídico dos transplantados renais é muito alta, sendo a doença cardiovascular uma das principais causas de mortalidade nesses pacientes. Mesmo após o transplante renal, as complicações cardíacas não diminuem. O objetivo foi avaliar o perfil lipídico de pacientes transplantados renais em uso de terapia imunossupressora e relacionar qual dos imunossupressores estaria associado a alterações no perfil lipídico. Métodos: Estudo retrospectivo realizado com 186 pacientes em terapia imunossupressora pós-transplante renal com ciclosporina, tacrolimus ou sirolimus. Foram coletadas amostras dos pacientes que realizaram transplante renal entre 2002 e 2007 , na Irmandade Santa Casa de Misericórdia de Porto Alegre, e que foram incluídos na pesquisa. Resultados: Foi observado que os níveis de colesterol aumentaram nos pacientes em uso de ciclosporina e sirolimus. O HDL-C mostrou-se mais elevado em todos os grupos, independente do tempo, após o transplante renal. Quanto ao LDL-C, verificou-se diminuição com o passar do tempo de tratamento no grupo que fazia uso de ciclosporina. A razão colesterol total/HDL-C diminuiu com o tratamento de ciclosporina e de tacrolimus após 24 meses. Conclusão: Os resultados sugerem que o tacrolimus e a ciclosporina são os imunossupressores menos prejudiciais ao perfil lipídico dos pacientes transplantados renais, no entanto, o sirolimus está associado à maior alteração no perfil lipídico, podendo levar os pacientes a um pior prognóstico cardíaco.