74 research outputs found
Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.This work was supported by the Medical Research Council [U106179472; MC_U106179472; U106179471; MC_U106179471] and the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981 to 23andMe). The UK Medical Research Council and Wellcome Trust (092731), together
with the University of Bristol, provide core support for the ALSPAC study. AMH assays in ALSPAC were funded with a grant from the US National Institute of Health (R01 DK077659). DAL works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_12013/5).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms946
Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): A cross-sectional study
Objective To compare vitamin D status in women with PCOS versus fertile women and subsequently evaluate the association between vitamin D status and metabolic disturbances in PCOS women. Methods We conducted a cross-sectional comparison study of 639 women with PCOS and 449 fertile women. Serum 25-hydroxyvitamin D (25(OH)D) was stratified into a severe deficient ( 75 nmol/l) status. The main outcome measures were the difference in vitamin D status between PCOS and fertile women, and the association between serum 25(OH)D and metabolic disturbances in PCOS women only. Results Serum 25(OH)D was significantly lower in PCOS women compared to fertile controls (mean 25(OH)D of 49.0 nmol/l versus 64.5 nmol/l). An adjusted significant difference was seen between serum 25(OH)D and homeostasis model assessment (HOMA-IR) (β = 0.76; 95% CI: 0.63–0.91; p < 0.01), HDL-cholesterol (β = 0.20; 95% CI: 0.05–0.60, p < 0.01) and apolipoprotein A1 (β = 26.2; 95% CI: 7.5–45.0, p < 0.01) between the highest vitamin D group compared to the lowest vitamin D group. Conclusions This study demonstrates that women
Loss of RNA–Dependent RNA Polymerase 2 (RDR2) Function Causes Widespread and Unexpected Changes in the Expression of Transposons, Genes, and 24-nt Small RNAs
Transposable elements (TEs) comprise a substantial portion of many eukaryotic genomes and are typically transcriptionally silenced. RNA–dependent RNA polymerase 2 (RDR2) is a component of the RNA–directed DNA methylation (RdDM) silencing pathway. In maize, loss of mediator of paramutation1 (mop1) encoded RDR2 function results in reactivation of transcriptionally silenced Mu transposons and a substantial reduction in the accumulation of 24 nt short-interfering RNAs (siRNAs) that recruit RNA silencing components. An RNA–seq experiment conducted on shoot apical meristems (SAMs) revealed that, as expected based on a model in which RDR2 generates 24 nt siRNAs that suppress expression, most differentially expressed DNA TEs (78%) were up-regulated in the mop1 mutant. In contrast, most differentially expressed retrotransposons (68%) were down-regulated. This striking difference suggests that distinct silencing mechanisms are applied to different silencing templates. In addition, >6,000 genes (24% of analyzed genes), including nearly 80% (286/361) of genes in chromatin modification pathways, were differentially expressed. Overall, two-thirds of differentially regulated genes were down-regulated in the mop1 mutant. This finding suggests that RDR2 plays a significant role in regulating the expression of not only transposons, but also of genes. A re-analysis of existing small RNA data identified both RDR2–sensitive and RDR2–resistant species of 24 nt siRNAs that we hypothesize may at least partially explain the complex changes in the expression of genes and transposons observed in the mop1 mutant
Polycystic ovary syndrome
The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Robert J Norman, Ruijin Wu and Marcin T Stankiewic
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
Cardiometabolic biomarkers in women with polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Apart from the reproductive problems, PCOS is also associated with metabolic disturbances, and therefore, it also affects adolescents and postmenopausal women with PCOS as well as their offspring and other first-degree relatives. Adolescents with PCOS show unfavorable cardiometabolic biomarkers more often than controls, such as overweight/obesity and hyperandrogenism, and studies also suggest an unfavorable lipid profile. During reproductive age, women with PCOS develop additional cardiometabolic biomarkers, such as hypertension, insulin resistance, and metabolic syndrome. Growing evidence also supports the important role of inflammatory cytokines in cardiovascular health in these women. During menopausal transition, some PCOS characteristics ameliorate, whereas other biomarkers increase, such as body mass index, insulin resistance, type 2 diabetes, and hypertension. Offspring of women with PCOS have a lower birth weight and a higher body mass index later in life than controls. In addition, fathers, mothers, and siblings of women with PCOS show unfavorable cardiometabolic biomarkers. Therefore, cardiovascular screening and follow-up of women with PCOS and their offspring and siblings are of utmost importance
The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review
Context: Metabolic disturbances, in particular, insulin resistance (IR) and dyslipidemia, are common in women suffering from polycystic ovary syndrome (PCOS). Evidence is accumulating that vitamin D status may contribute to the development of metabolic disturbances in PCOS. Objective: The aim of this study was to carry out a systematic review addressing the association between vitamin D status, vitamin D receptor polymorphisms, and/or polymorphisms related to vitamin D metabolism and metabolic disturbances in women with PCOS. Design and methods: A systematic search of electronic databases was carried out up to January 2013 for observational studies and clinical trials in women suffering from PCOS with outcome measures that were related to vitamin D status. We conducted univariate and multivariate regression analyses of the weighted means to gain insights into the association between vitamin D, BMI, and IR based on existing literature. Results: We found 29 eligible trials with inconsistency in their results. One well-designed randomized controlled trial has been carried out until now. Univariate regression analyses of the weighted means revealed vitamin D to be a significant and independent predictor of IR in both PCOS and control women. The significance disappeared after adjustment for BMI in PCOS women. Conclusions: Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. The causal relationship between vitamin D status and metabolic disturbances in PCOS remains to be determined in well-designed placebo-controlled randomized clinical trials. © 2013 European Society of Endocrinology
Genetic Ancestry Affects the Phenotype of Normogonadotropic Anovulatory (WHOII) Subfertility
Introduction: Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. Objective: Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio-geographic ancestry and predict the phenotype of individual patients. Materials and Methods: A standardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. Results: Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structure on a continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. Conclusion: Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility. (J Clin Endocrinol Metab 96: E1181-E1187, 2011
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