Analysis of vitamin D receptor gene (VDR) polymorphisms in Turner syndrome patients

Individuals with Turner syndrome (TS) have increased risk for autoimmune diseases, especially thyroid abnormalities. The function of the vitamin D receptor (VDR) gene is influenced by several genetic polymorphisms which are associated with a susceptibility to a range of autoimmune diseases. Thus, we have hypothesized a possible relationship between thyroid abnormalities and VDR polymorphisms (ApaI/G1025-49T, TaqI/T1056C, FokI/T2C and BsmI G1024?+?283A) in TS patients. A case-control study was performed comprising 101 Brazilian women with TS and a control group consisting of 133 healthy fertile women without a history of autoimmune diseases. In TS group, 21.8% had Hashimoto's thyroiditis. Detection of VDR polymorphisms was performed using TaqMan system by real-time PCR. The χ(2) was used to compare allele and genotype frequencies between groups. Combined genotypes of VDR gene polymorphisms were assessed by the haplotype analysis. A p value <0.05 was considered statistically significant. Relatively similar VDR polymorphisms genotype and allelic frequencies in cases and controls were found, even when only considering the patients with thyroid abnormalities. Haplotype analysis showed that none of the VDR haplotypes were associated to thyroid diseases in TS patients. In conclusion, the results showed no association between VDR gene polymorphisms and thyroid abnormalities in Brazilian TS patients tested.     

Polymorphisms in vitamin D receptor gene,but not vitamin D levels,are associated with polycystic ovary syndrome in Brazilian women

This study aimed to investigate the association between vitamin D (VitD) levels, polymorphisms in VDR gene (ApaI, BsmI, FokI, and TaqI) and the polycystic ovary syndrome (PCOS) in a group of Brazilian women. A total of 100 patients with PCOS and 100 control women were included. The quantification of 25-hydroxyvitamin D (25(OH)D) was performed in high-performance liquid chromatography (HPLC). Polymorphisms on VDR gene were performed by PCR-RFLP. The BsmI AG genotype was more frequent in PCOS group, while the GG genotype was more frequent in the control group (p?=?.007). The frequency of the Taql CC genotype was higher in PCOS group, while the CT genotype was the most frequent in the control group (p?=?.021). Mean serum VitD levels were similar between the groups. However, there was a negative correlation between VitD levels and Ferriman-Gallwey score (p?=?.031, r?=??.260) in the PCOS group. The TaqI and BsmI polymorphisms were associated with PCOS. Moreover, VitD levels are associated with the clinical hyperandrogenism. The data suggest the role of VitD in PCOS development and its complications.     

The role of vitamin D receptor genes (FOKI and BSMI) polymorphism in osteoporosis

ObjectiveTo evaluate the pattern of vitamin D receptor (VDR) genes polymorphism in postmenopausal Egyptian females for possible genetic role.DesignProspective cross sectional study.Participants and methodsEgyptian postmenopausal women with and without osteoporosis were diagnosed by bone mineral density measurement then were subjected to identification of VDR genes (FOKI and BSMI) polymorphism by PCR technique followed by RFLP analysis.ResultsThe frequencies of BB, Bb and bb genotypes (BSMI polymorphism) in patients were 54%, 30% and 16%, respectively. While, in controls their frequency was 5%, 10% and 85%, respectively. The BB genotype was higher in patients than in controls (P=0.001) while the bb genotype was significantly higher in controls than in patients. Regarding the FOKI polymorphism the frequencies of FF, Ff and ff genotypes among patients were 68%, 18% and 14%, respectively while their frequency in controls were 100%, 0% and 0%, respectively. Postmenopausal females carrying either B+ve or f+ve genotype were more risky to develop osteoporosis (OR of 29.75, 1.59, respectively).ConclusionThe BB genotype was higher in patients than controls and the bb genotype is a protective genotype. The FF genotype was predominant among post menopausal females and ff genotype was associated with osteoporosis. Currently, however, the mechanisms by which VDR alleles regulate BMD remain poorly understood.     

Vitamin D receptor gene polymorphism and cardiovascular risk variables in elderly Polish subjects

The aim of this work was to evaluate whether the FokI and BsmI polymorphisms of the VDR gene are associated with anthropometric and biochemical features of cardiovascular disease (CVD) in a Caucasian population aged over 65, participants of the Polish PolSenior study. We performed the study on randomly selected subjects: 427 women and 454 men aged over 65. Measurements of anthropometric parameters were carried out and biochemical parameters were estimated using commercial kits. VDR polymorphisms (rs10735810, rs1544410) were genotyped by PCR and FRLP. The prevalence of BsmI genotypes was 50% Bb, 23% bb, 27% BB in women and 48% Bb, 20% bb, 32% BB in men. The prevalence of FokI was 48% Ff, 22% ff, 30% FF in women and 50% Ff, 18% ff, 32% FF in men. The women bearing the rare allele b differ in homeostatic model assessment (HOMA) (p < 0.049) from women bearing common allele B, and the men differ in insulin level (p < 0.047) and HOMA (p < 0.017). There were no significant differences in anthropometric or biochemical parameters between genotypes in FokI in female and male groups. The common allele B is connected with biochemical risk factors of CVD in older Caucasian men and women.     

Brain-derived neurotrophic factor plasma levels in patients with Turner syndrome

Introduction: Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and synaptic plasticity. BDNF is known to circulate in plasma and its levels are strictly linked to the sex hormones.

Aim: The aim of this study was to assess the plasma BDNF concentration in patients with Turner syndrome (TS). This is a first of such study in TS women.

Methods: 31 TS patients were enrolled to the study and compared with a control group (10 healthy, ovulatory women). We collected blood for measurement of BDNF plasma concentration, estradiol (E2) and gonadotrophins serum levels. The blood was taken after overnight fasting, in menstruating women in follicular phase.

Results: We found that BDNF plasma concentration was significantly higher in the group of TS patients compared to the control group (mean 768.5?±?194.9?pg/ml versus 407.2?±?25.7?pg/ml; p?r?=?0.92; p?Conclusions: In this study, we showed for the first time that TS patients has a higher BDNF levels than healthy ones and BDNF is not correlated with E2 concentration but tend to be related to testosterone. This study brings interesting insights to BDNF physiology.     

Molecular identification of chromosome Y sequences in Brazilian patients with Turner syndrome

The investigation of Y-specific sequences in patients with Turner Syndrome (TS) with karyotype 45,X or mosaic, has a fundamental role in the clinical management of these patients. The relationship between the presence of Y chromosome fragments and a higher risk of gonadoblastoma in TS has already been established. The aim of the study was to investigate the presence of Y-chromosome fragments in a population of 42 female Brazilian patients with TS from Mato Grosso state. Cytogenetic analysis has shown the karyotypes 45,X in 27 of them (64.3%) and mosaic in 15 (35.7%). The presence of the Y-primers SRY, DYZ3, ZFY, DYZ1, DYS1 and PABY was investigated in all patients. These markers were amplified by polymerase chain reaction (PCR) technique, using DNA genomic from peripheral blood lymphocytes. None of these patients had shown any Y-chromosome fragments when they were analysed only by the classic cytogenetic technique. The PCR analysis with the Y-specific sequences ZFY and DYZ3 were identified in two different patients (4.8%), both with karyotype 45,X. It was concluded that PCR is efficient in the investigation of hidden Y-fragments in TS patients. Therefore, this method should be included in the routine assistance of these patients.     

Low bone mineral density and renal malformation in Mexican patients with Turner syndrome are associated with single nucleotide variants in vitamin D-metabolism genes

Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene–gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them.     

维生素D受体基因多态性与佝偻病关系的研究

探讨维生素D受体基因多态性与维生素D缺乏性佝偻病（佝偻病）遗传易感性的关系。方法 　应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP ）分析技术检测2003年10月至2004年10月159例佝偻病患儿和78名健康儿童（对照组）VDR基因BsmⅠ位点的多态性,比较两组之间VDR基因型和基因分布。结果　 佝偻病患儿和对照组儿童的VDR基因Bsm I位点基因型分布分别为：BB（0％）,Bb（15.7％）,bb（84.3％）和BB（0％）,Bb（11.5％）,bb（88.5％）,两组 间差异无统计学意义（P >0.05）;佝偻病患儿和对照组儿童的VDR基因Bsm I位点等位基因分布分别为：B（7.9％）,b（92.1％）和B（5.8％）,b（94.2％）, 两组间差异无统计学意义（P > 0.05）。结论　VDR基因BsmⅠ酶切位点的多态性与维生素D缺乏性佝偻病的遗传易感性相关关系尚须大样本进一步确定。     

The vitamin D receptor gene BsmI polymorphism is not associated with anthropometric and biochemical parameters describing metabolic syndrome in postmenopausal women

Aim. Vitamin D could have a direct effect on adipocyte differentiation and metabolism and might be involved in glucose regulation of insulin secretion. In recent years several polymorphisms in the gene encoding the vitamin D receptor (VDR), which are potent to alter the activity of VDR protein, have been described. The present study aimed to investigate the prevalence of the VDR BsmI polymorphism and its association with anthropometric and biochemical features of metabolic syndrome in postmenopausal women.

Materials and methods. We studied 351 randomly selected healthy postmenopausal women, with mean age of 55.43 ± 2.75 years and mean body mass index (BMI) of 27.5 ± 4.78 kg/m², to evaluate the frequency of BsmI polymorphism (by restriction fragment length polymorphism–polymerase chain reaction) in the VDR gene and to find out whether there is an association between this polymorphism and BMI, total fat volume and visceral fat (as determined by total body dual-energy X-ray absorptiometry), blood pressure, lipid profile (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides) glucose and fasting insulin in the whole group, as well as subgroups of obese and non-obese women.

Results. The prevalence of BsmI genotypes in the study group was 51.0% Bb, 37.3% bb and 11.7% BB. Genotype distribution did not differ from that expected under Hardy–Weinberg equilibrium conditions (χ² = 2.95, p = 0.22). Apart from LDL-C levels (F = 3.46, p = 0.032), there were no significant differences in anthropometric or metabolic parameters between genotypes.

Conclusions. The BsmI polymorphism in the VDR gene does not seem to predispose to obesity and insulin resistance, but the BB genotype is connected with an unfavorable lipid profile.     

Turner综合征Y染色体物质嵌合分子遗传学研究

摘要：目的　分析Turner综合征（TS）患儿Y染色体物质及衍生物嵌合发生的情况,为TS患儿诊断后的监测提供科学建议,改善国内TS监测和保健管理的现状。方法　选取2006年2月至2007年8月在重庆医科大学附属儿童医院诊断为TS患儿30例,进行基因组DNA 的Y编码睾丸特异性蛋白基因（TSPY）、 Y染色体中心着丝粒DYZ3重复序列（DYZ3 ）和Y性别决定区域（SRY）3个Y染色体特异序列多聚酶链反应（PCR）检测,反应结果阳性的病例补充SRY探针原位荧光杂交（FISH）分析。结果　基因组DNA 的PCR结果显示,3例患儿的TSPY、 DYZ3扩增均为阳性（10.00%）,其中只有1例 SRY 扩增阳性（3.33%）;3例Y染色体物质阳性病例进一步进行FISH研究,结果显示3例SRY杂交信号均为阳性。结论　运用3个Y染色体特异序列的分子遗传学研究,证实Y染色体物质嵌合在TS不少见,每一个TS患儿都应在诊断后进行Y染色体物质的分子遗传学监测。     

Turner syndrome and pregnancy: clinical practice. Recommendations for the management of patients with Turner syndrome before and during pregnancy

Following the death in France by acute aortic dissection of two women with Turner syndrome who were pregnant following oocyte donation, the Director of the French Biomedicine Agency (Agence de la biomédecine) sent a letter to the President of the French College of Obstetricians and Gynaecologists (FCOG). He requested the College's expertise in reviewing point-by-point the cases and risk factors and in determining whether there are grounds to propose additional measures complementary to the recommendations made by the Haute autorité de santé or French National Authority for Health (HAS) in 2008 in terms of indication and monitoring of patients. A joint practice committee of the FCOG, the French Cardiologic Society, the French Chest and Cardiovascular Surgery Society, the French Society of Anaesthesia and Intensive Care, the French Endocrine Society, the French study group for oocyte donation, and the Biomedicine Agency defined the exact questions to be put to the experts, chose these experts, followed them up and drafted the synthesis of recommendations resulting from their work.The questions concerned the check-up before pregnancy of Turner patients, contraindication and acceptance of pregnancy, information for the patients, and recommendations for antenatal care, delivery and postnatal follow-up.     

VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications

The aim of the study is evaluating the associations of FokI vitamin D receptor (VDR) gene polymorphisms with gestational diabetes mellitus (GDM), and its relations with postpartum metabolic syndrome. In a cohort study, 303 women referred to outpatient clinic of Shariati Hospital. The VDR FokI genotypes were determined. All subjects were followed 6–12 weeks after delivery. The frequencies of Ff, FF, and ff genotypes were 30.4% (49), 63.4% (102), and 6.2% (10), respectively, in healthy pregnancies and 34.5% (49), 54.9% (78), and 10.6% (15), respectively, in GDM patients. The ff genotype was more common in GDM patients. Healthy individuals had higher frequency of F allele, suggesting that F allele may have a role in decreased incidence of GDM. Concerning the GDM risk factors, f allele had significant association with prepregnancy obesity and family history of diabetes. In postpartum follow-up, women who developed metabolic syndrome were significantly older with higher prepregnancy body mass index, had more family history of diabetes, and also their ff genotype was two fold more frequent. Our results indicate a meaningful association between FokI VDR genotypes and an increase risk of GDM in Iranian population as well as its effects on postpartum metabolic syndrome.     

维生素D受体基因多态性与中国汉族儿童结核病易感性的研究

目的　探讨维生素D受体（VDR）基因多态性与中国汉族儿童结核病易感性的关系。 方法　收集2005年1月至2008年3月北京儿童医院收治的125例汉族儿童 结核病患儿,以同期在北京儿童医院门诊行外科手术（如疝、牙齿矫正、鞘膜积液等）前查体的446例患儿作为对照,对照组无结核病史,X线胸片无异常,PPD皮 试硬结直径小于5 mm,按照年龄、性别以及居住地与病例组进行匹配,采用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）检测VDR基因上的Fok I和Taq I位点多态性,采用SPSS 12.0软件对病例组和对照组的基因型和等位基因频率进行卡方检验。 结果　结核组和对照组Fok I位点的FF、Ff、ff基因型频率分别为 29.6%、51.2%、19.2%和27.6%、50.9%、21.5%;Taq I位点的TT、Tt、tt基因型频率分别为90.4%、9.6%、0和86.8%、13.0%、0.2%;结核组和对照组在基因型频率 和等位基因频率分布上差异均无统计学意义。将样本按性别进行分组比较后发现,不同性别中病例组和对照组儿童的基因型和等位基因频率之间的差异无统计学 意义。 结论　VDR基因上的Fok I和Taq I位点的多态性与中国汉族儿童结核病的易感性无明显相关性。     

Turner综合征患者标记染色体的鉴定与分析

目的 分析11例携带标记染色体的Turner综合征患者的核型,研究这类染色体的表型效应。方法 选择11例具Turner综合征表型的患者,常规核型分析均显示为携带标记染色体的嵌合体,其中6例标记染色体呈环状。患者G带核型表示为mos．45,X／46,X,＋mar或者mos．45,X／46,X,＋r．以X／Y着丝粒探针,应用荧光原位杂交（FISH）技术分析这些标记染色体起源,对其中2例较大的环状染色体,结合反向染色体涂染确定断裂位点,比较不同断裂位点的标记染色体的遗传学效应。结果11例患者所携带的标记染色体均为环状染色体,r（X）的断裂位点分别位于Xp22、Xq22、Xq24、Xq26等。结论 Turner综合征患者的标记染色体主要来源于X染色体,且表现为r（X）形式。r（X）均以嵌合型的形式存在。     

The relationship of the Fas 670 A/G gene polymorphism with cardiovascular risk factors in polycystic ovary syndrome (PCOS) patients

Aims.?Apoptosis has been shown in cardiac cells under divergent physiological and pathological conditions. Apoptosis plays a key role in the pathogenesis of cardiac diseases. We aimed to evaluate the relation between Fas 670 A/G gene polymorphism in polycystic ovary syndrome (PCOS) patients carrying a potential risk for developing cardiovascular disease (CVD).

Materials and methods.?Ninety-one patients with PCOS and 100 cases of healthy control people were included in this study. PCOS was defined by the Rotterdam PCOS consensus criteria. The evaluation of genotype for Fas 670 A/G gene polymorphism was performed by using PCR-RFLP method.

Results.?The evaluation of Fas genotype and gene allele frequency did not show statistically significant difference between patient and control groups. Both in PCOS patients and control groups, there were no statistically significant differences among A/A, A/G, and G/G.

Conclusions.?We found no relation between the cardiovascular risk factors and Fas 670 A/G gene polymorphism in women with PCOS and healthy subjects. Our results in risk factors of CVD can probably be explained by the fact that metabolic parameters and endothelial systems of the patients may not be affected yet in this short period of time.     

Psychological well-being in women with Turner syndrome: Somatic and social correlates

Our aim was to examine possible somatic and social correlates to psychological well-being in adult women with Turner Syndrome (TS), including hormone replacement treatment. Sixty-three women with a diagnosis of TS (mean age, 31.5 years) participated in a cross-sectional study, using interview data, ratings on the Psychological General Well-being (PGWB) Index, and data from medical examinations and medical records. Statistical analysis was performed by bivariate and multivariate analyses. Lack of sex hormones during adult life and the presence of hearing impairment were related to lower psychological well-being, as were higher age at diagnosis, higher age at menarche or induced bleeding, higher chronological age and retrospectively reported difficulties with school subjects. Age at diagnosis and difficulties with school subjects explained 25% of the variation in psychological well-being. This study has identified some correlates to psychological well-being in women with TS, which are important when considering the clinical management of adult women with TS.