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- ItemAcesso aberto (Open Access)Análise do polimorfismo do gene do receptor de melatonina mtnr1b em mulheres com síndrome dos ovários policisticos em uso de metformina e antinconcepcional(Universidade Federal de São Paulo (UNIFESP), 2014-02-12) Iwata, Margareth Chiharu [UNIFESP]; Soares Junior, Jose Maria [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)INTRODUCTION.The polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive age in women. The exact pathophysiological mechanism of the syndrome remains unclear, but it is believed that insulin and its receptor are involved. Hyperinsulinemia and its receptor defect. may contribute to the onset of ovarian and systemic hyperandrogenism as well as chronic anovulation. Melatonin is a hormone that can regulate insulin receptor sensitivity by tyrosine phosphorylation and also act on insulin secretion by pancreatic beta cells by MT2 receptor. Therefore, melatonin may be related to carbohydrate metabolism and thus, with PCOS pathogenesis. Studies have associated genetic alterations in MTNR1B gene encoding MT2 receptor with risk of developing type 2 diabetes. Another point in the PCOS would be the worsening of glucose tolerance with use of contraceptives, and patients with these polymorphisms could have worse outcome. Furthermore, if metformin was given, perhaps its action was not as effective. Therefore, we sought to evaluate the response of adolescents with PCOS using metformin and combined oral contraceptive, and analyze the influence of melatonin receptor gene polymorphisms in these patients. OBJECTIVE. identify four genetic polymorphisms of type 2 melatonin receptor correlating them with plasma glucose, plasma insulin and sex steroids; evaluate the use of insulin sensitizing drug (metformin) and therapy using etnilestradiol and cyproterone in adolescents with PCOS. METHODS. Prospective, randomized, double blind, placebo controlled clinical trial in adolescents with PCOS by Rotterdam criteria (2003), divided into group 1 - contraceptive (35 mcg ethinylestradiol + 2 mg of cyproterone acetate) and metformin 1500 mg / day; Group 2 - contraceptive and placebo. Time use: 6 months. Clinical parameters (BMI, waist-hip ratio, blood pressure, acanthosis nigricans, hirsutism, acne) and laboratory (AST, ALT, creatinine, FSH, LH, estradiol, total testosterone, androstenedione, SHBG, fasting and 2 hours after overload glucose and insulin, total cholesterol, HDL, LDL, triglycerides, melatonin) were evaluated. Polymorphisms rs10830963 C/G, rs12804291 C/T, rs3781638 A/C, 1387153 C/T by PCR and DNA sequencing. RESULTS. Polymorphisms were evaluated in 106 patients and the response to medication in 45 of them. Clinical improvement of hyperandrogenism was higher in the metformin and oral contraceptive group and not determined significant weight gain. Oral contraceptive plus placebo group showed significant increase in body mass index. Metformin and contraceptive determined marked reduction of LH, free testosterone and blood glucose and insulin parameters than in the placebo plus contraceptive after six months of treatment. There was no significant change in melatonin levels during the study. Adverse effects were greater in metformin plus contraceptive group. In the data before treatment, the polymorphism rs10830963 C/G determined higher values of fasting glucose; and rs3781638 polymorphism A/C determined lower insulin levels after glucose overload. During treatment, the polymorphism rs1387153 C/T determined elevated blood glucose levels, while rs12804291C/T and rs3781638 A/C determined increase and decrease, respectively, of total testosterone. CONCLUSIONS. The use of metformin may be safe in adolescents and the association of metformin may provide additional benefit in these patients, particularly in relation to body weight, carbohydrate metabolism and hyperandrogenism. MTNR1B gene polymorphisms are associated with metabolism of glucose and insulin and may influence the response to treatment with metformin and combined oral contraceptive.
- ItemSomente MetadadadosAngiotensinogen and angiotensin converting enzyme gene polymorphisms and the risk of bipolar affective disorder in humans(Elsevier B.V., 2000-10-27) Meira-Lima, IV; Pereira, A. C.; Mota, GFA; Krieger, J. E.; Vallada, H.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)A possible participation of the renin-angiotensin system (RAS) components with mood disturbances has been suggested in both animal and pharmacological models. in this cross-sectional study, we examined the association between functional polymorphisms in the angiotensin converting enzyme (ACE) and angiotensinogen (AGI) genes in 115 bipolar affective disorder (BPAD) patients and 323 healthy control subjects. the ACE I/D variant did not show any difference in allelic frequencies and genotypic distribution between the groups. in contrast, when studying the AGT M235T polymorphism we found that the M allele was more frequently observed in BPAD patients than in controls (chi (2) = 6.766, d.f. = 1, P = 0.009). Using multivariate logistic models the strongest odds ratio resulted from a dominant genetic model (OR = 3.0; CI (95%) 1.7-5.3] Our data suggest an association between the AGT M235 genotype and increased susceptibility for BPAD in these Brazilian patients. These findings are consistent with the hypothesis that the RAS system plays a role in regulating the mood (C) 2000 Published by Elsevier Science Ireland Ltd.
- ItemSomente MetadadadosAssociation and linkage studies between bipolar affective disorder and the polymorphic CAG/CTG repeat loci ERDA1, SEF2-1B, MAB21L and KCNN3(Nature Publishing Group, 2001-09-01) Meira-Lima, Ivanor Velloso [UNIFESP]; Zhao, J.; Sham, P.; Pereira, A. C.; Krieger, J. E.; Vallada, H.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Inst PsychiatSeveral reports have suggested the presence of anticipation in bipolar affective disorder (BPAD). in addition, independent studies using the RED (repeat expansion detection) have shown association between BPAD and longer CAG/CTG repeats. Therefore loci with large CAG/CTG repeats are plausible candidates in the inheritance of BPAD. the present study assesses the length of the repeats in four loci: the ERDA-1 locus which is known to account for most of the long CAG repeats detected by RED, the SEF2-1b locus which is placed in a region where positive linkage results have been reported and the loci MAB21L and KCNN3 as functional candidate genes. A Brazilian case-control sample with 115 unrelated BPAD patients and 196 healthy control subjects and 14 multiply affected bipolar families was investigated. With the case-control design the distribution of alleles between the two groups did not approach statistical significance. the extended transmission disequilibrium test (ETDT) performed in our families did not show evidence for linkage disequilibrium. Parametric and non-parametric linkage analysis also did not provide support for linkage between any of the four loci and BPAD. Our data do not support the hypothesis that variation at the polymorphic CAG/CTG repeat loci ERDA-1, SEF2-1b, MAB21L or KCNN3 influence susceptibility to BPAD in our sample.
- ItemSomente MetadadadosCytokine gene polymorphisms in preeclampsia and eclampsia(Nature Publishing Group, 2009-07-01) Barbosa de Lima, Telmo H.; Sass, Nelson [UNIFESP]; Mattar, Rosiane [UNIFESP]; Moron, Antonio Fernandes [UNIFESP]; Torloni, Maria Regina [UNIFESP]; Franchim, Camila Sommerauer [UNIFESP]; Daher, Silvia [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Alagoas State UnivThe clinical spectrum of preeclampsia ( PE) ranges from mild hypertension to severe vasospasm associated with convulsions and multiple organ damage. the biological factors that determine the progression of PE to eclampsia ( E) are unknown. Endothelial cell activation seems related to an impaired maternal immune response. the production of cytokines, IL-10 and TGF-beta 1, is apparently suppressed, and altered IL-2/IL-10 and TNF-alpha/IL-10 ratios have been reported in preeclamptic cases. the relationship between PE and cytokine gene polymorphism has been studied, but there are few studies that include eclamptic patients. This study aimed at investigating whether polymorphisms in genes, TNF-alpha promoter (-308 G>A), IL6 promoter (-174 G>C), IFN-gamma intron 1 (+874 A>T), IL10 promoters (-1082 A>G), (-819 C>T) and (-592 C>A) and TGF-beta 1 codon 10 (+869 T>C) and codon 25 (+915 G>C) are associated with E and/or PE. Genotyping was carried out in 266 Mulatto women from the northeastern region of Brazil who were referred to a single maternity hospital: 92 with PE, 73 with E and 101 normotensive controls. the chi(2) or Fisher's exact tests were used to compare genotype frequencies. Among the six single-nucleotide polymorphisms ( SNPs) studied, we found no difference in genotype frequencies between the groups. There was a higher frequency of IFN-gamma (+874 A) in eclamptic patients in comparison with that in controls. (70.3 vs. 57.8%, respectively; P=0.02). There were no other significant differences in allelic frequencies between eclamptic, preeclamptic and control groups We found no independent association between any single SNP and PE or E risk in this population of Mulatto women from the northeastern region of Brazil. Hypertension Research ( 2009) 32, 565-569; doi: 10.1038/hr.2009.58; published online 1 May 2009
- ItemSomente MetadadadosDiscovery Properties of Genome-wide Association Signals From Cumulatively Combined Data Sets(Oxford Univ Press Inc, 2009-11-15) Pereira, Tiago da Veiga [UNIFESP]; Patsopoulos, Nikolaos A.; Salanti, Georgia; Ioannidis, John P. A.; Univ Ioannina; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Fdn Res & Technol Hellas; Tufts UnivGenetic effects for common variants affecting complex disease risk are subtle. Single genome-wide association (GWA) studies are typically underpowered to detect these effects, and combination of several GWA data sets is needed to enhance discovery. the authors investigated the properties of the discovery process in simulated cumulative meta-analyses of GWA study-derived signals allowing for potential genetic model misspecification and between-study heterogeneity. Variants with null effects on average (but also between-data set heterogeneity) could yield false-positive associations with seemingly homogeneous effects. Random effects had higher than appropriate false-positive rates when there were few data sets. the log-additive model had the lowest false-positive rate. Under heterogeneity, random-effects meta-analyses of 2-10 data sets averaging 1,000 cases/1,000 controls each did not increase power, or the meta-analysis was even less powerful than a single study (power desert). Upward bias in effect estimates and underestimation of between-study heterogeneity were common. Fixed-effects calculations avoided power deserts and maximized discovery of association signals at the expense of much higher false-positive rates. Therefore, random- and fixed-effects models are preferable for different purposes (fixed effects for initial screenings, random effects for generalizability applications). These results may have broader implications for the design and interpretation of large-scale multiteam collaborative studies discovering common gene variants.
- ItemSomente MetadadadosGenetic Polymorphisms and Recurrent Spontaneous Abortions: An Overview of Current Knowledge(Wiley-Blackwell, 2012-04-01) Daher, Silvia [UNIFESP]; Mattar, Rosiane [UNIFESP]; Gueuvoghlanian-Silva, Barbara Y. [UNIFESP]; Torloni, Maria R. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)The relevance of gene polymorphisms in the development of unexplained recurrent spontaneous abortion is still unclear. Cytokines, angiogenic mediators, and hormones are involved in all stages of reproduction and pregnancy outcome. Impaired production and/or unbalanced ratios of these mediators have been implicated in the pathogenesis of unexplained recurrent spontaneous abortion. Functional polymorphism influence gene activity and therefore can interfere with the expression of mediators. Several studies have been carried out to evaluate the relationship between cytokines, angiogenic mediators, and hormones gene polymorphisms and unexplained recurrent spontaneous abortion. the results of these studies are mostly contradictory, and few significant associations have been identified. Up to present time, the evidence is insufficient to support the evaluation of cytokines, angiogenic mediators, and hormones gene polymorphism in routine workup in all cases of recurrent pregnancy loss, and these tests are not included in any of the major obstetric guidelines.
- ItemSomente MetadadadosThe human leucocyte antigen DQB1*0602 allele is associated with electroencephelograph differences in individuals with obstructive sleep apnoea syndrome(Wiley-Blackwell, 2013-04-01) Manzotte, Thais [UNIFESP]; Guindalini, Camila [UNIFESP]; Mazzotti, Diego R. [UNIFESP]; Palombini, Luciana [UNIFESP]; De Souza, Altay L. [UNIFESP]; Poyares, Dalva [UNIFESP]; Bittencourt, Lia R. A. [UNIFESP]; Tufik, Sergio [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Human leucocyte antigen (HLA) DQB1*0602 allele, a well-known genetic risk factor for narcolepsy, has been associated with sleep parameters in healthy subjects. We aimed to assess the association of this allele with daytime sleepiness and altered sleep electroencephalogram characteristics in the general population and in patients with obstructive sleep apnoea syndrome (OSAS). Eight hundred and ninety-four individuals from the Epidemiologic Study of Sleep were genotyped for the HLA DQB1*0602 allele. Full-night polysomnography was performed, and daytime sleepiness was analysed according to the Epworth Sleepiness Scale. HLA-DQB1*0602 allele-positive and -negative subjects in the general population, as well as in patients with OSAS, exhibited similar sleep parameters and levels of daytime sleepiness. However, spectral analysis showed that allele-positive individuals with OSAS exhibited higher theta power during sleep Stage 1 (P<0.05) in occipital derivations, and lower delta power during sleep Stages 1 and 2 (P<0.01) compared with individuals negative for the allele, even after correction for potential confounders as age, sex, body mass index and European ancestry. No significant differences in the electroencephalogram variables were found in individuals without OSAS. the data highlight the HLA-DQB1*0602 as a potential genetic factor influencing sleep physiology in individuals diagnosed with OSAS.