A new tissue-agnostic microfluidic device to model physiology and disease: the lattice platform.

To accurately phenocopy human biology in vitro, researchers have been reducing their dependence on standard, static two-dimensional (2D) cultures and instead are moving towards three-dimensional (3D) and/or multicellular culture techniques. While these culture innovations are becoming more commonplace, there is a growing body of research that illustrates the benefits and even necessity of recapitulating the dynamic flow of nutrients, gas, waste exchange and tissue interactions that occur in vivo. However, cost and engineering complexity are two main factors that hinder the adoption of these technologies and incorporation into standard laboratory workflows. We developed LATTICE, a plug-and-play microfluidic platform able to house up to eight large tissue or organ models that can be cultured individually or in an interconnected fashion. The functionality of the platform to model both healthy and diseased tissue states was demonstrated using 3D cultures of reproductive tissues including murine ovarian tissues and human fallopian tube explants (hFTE). When exogenously exposed to pathological doses of gonadotropins and androgens to mimic the endocrinology of polycystic ovarian syndrome (PCOS), subsequent ovarian follicle development, hormone production and ovulation copied key features of this endocrinopathy. Further, hFTE cilia beating decreased significantly only when experiencing continuous media exchanges. We were then able to endogenously recreate this phenotype on the platform by dynamically co-culturing the PCOS ovary and hFTE. LATTICE was designed to be customizable with flexibility in 3D culture formats and can serve as a powerful automated tool to enable the study of tissue and cellular dynamics in health and disease in all fields of research.

Exposure of human fallopian tube epithelium to elevated testosterone results in alteration of cilia gene expression and beating.

STUDY QUESTION: How does exposure to a testosterone rich environment affect the function and gene expression of human fallopian tube epithelium (hFTE)? SUMMARY ANSWER: Elevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating. WHAT IS KNOWN ALREADY: The presence of estrogen in the follicular phase of the menstrual cycle increases the human fallopian tube ciliary beating frequency. The luteal phase, triggered by ovulation and increasing progesterone, is marked by a decrease in ciliary beating. Women with polycystic ovarian syndrome (PCOS) may have twice the serum level of testosterone than ovulatory women. To date, the effect of elevated androgens on the function of the human fallopian tube is not well-understood. We chose to examine the impact of elevated testosterone on hFTE. STUDY DESIGN, SIZE, DURATION: A prospective basic science study of human fallopian tube specimens from reproductive-aged women undergoing benign gynecologic surgery was performed. Fallopian tube removal at a large US academic center was collected and provided to us to continue with epithelium isolation and culturing. A total of 12 patients were analyzed in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fallopian tube epithelium was isolated and exposed to two different conditions: normal with low testosterone concentration of 0.8 nM and PCOS-like, with high testosterone concentration of 2 nM. The study was conducted in both static and dynamic conditions in microfluidic devices for a total of 14 days, after which the tissue was collected for processing including RNA extraction, quantitative PCR and immunohistochemistry. After the first 7 days of each experiment, a sample of tissue from each condition was imaged to quantify cilia beating frequency. MAIN RESULTS AND THE ROLE OF CHANCE: hFTE exposed to the 2 nM testosterone displayed slower cilia beating, inhibited estrogen signaling and decreased expression of the ciliary marker FOXJ1 when compared to stimulation with 0.8 nM testosterone. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The in vivo response to elevated testosterone may differ from in vitro studies. RNA amount was limited from tissue cultured in the microfluidic devices as compared to static culture. WIDER IMPLICATIONS OF THE FINDINGS: Understanding elevated testosterone in tubal function may explain an additional contribution to subfertility in women with PCOS and other hyper-androgen disorders, aside from oligo-ovulation. Furthermore, this adds to the body of literature of fallopian tube function using a microfluidic device. STUDY FUNDING/COMPETING INTEREST(S): NIH grants: UH3 ES029073 and R01 CA240301. There are no competing interests.

Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS. METHODS AND FINDINGS: Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25-32], body mass index [BMI] = 35.4 [28.2-41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24-33], BMI = 35.7 [28.4-42.3]). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a "metabolic" group (37%-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10-10; IQCA1, P = 2.8 × 10-9; BMPR1B/UNC5C, P = 9.7 × 10-9; CDH10, P = 1.2 × 10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10-8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25-33], BMI = 34.3 [27.8-42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated. CONCLUSIONS: In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data.

Publisher Correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Polygenic and Phenotypic Risk Prediction for Polycystic Ovary Syndrome Evaluated by Phenome-Wide Association Studies.

CONTEXT: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice. OBJECTIVE: Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment. DESIGN, PATIENTS, AND METHODS: Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS. RESULTS: The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity", "type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension", and "sleep apnea" reaching phenome-wide significance. CONCLUSIONS: Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome-phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.

Hyperandrogenemia is Common in Asymptomatic Women and is Associated with Increased Metabolic Risk.

OBJECTIVE: Women with metabolic syndrome (MetS) have higher endogenous testosterone (T) levels than unaffected women. This study investigated whether hyperandrogenemia (HA) was a marker for increased cardiometabolic risk in reproductively normal premenopausal women. METHODS: Reproductive hormones and metabolic parameters were assessed in 198 women with regular menses and no clinical hyperandrogenism (eumenorrheic [EM]). Hyperandrogenic EM women were compared with 110 women with NIH criteria polycystic ovary syndrome. RESULTS: Twenty-two percent of EM women had HA. Levels of non-sex hormone-binding globulin (SHBG)-bound T were elevated in 68% of women, total T levels were elevated in 43% of women, and dehydroepiandrosterone sulfate levels were elevated in 30% of women. The prevalence of HA increased with BMI category (P = 0.01): 12% for BMI < 25 kg/m2 , 22% for BMI of 25 to 30 kg/m2 , and 31% for BMI ≥ 30 kg/m2 . MetS (adjusted odds ratio 2.9; 95% CI: 1.2-6.9) and dysglycemia risks (adjusted odds ratio 2.7; 95% CI: 1.2-5.8) were increased in hyperandrogenic EM women compared with normoandrogenic EM women, with adjustment for BMI. SHBG levels were independently associated with these metabolic end points (P < 0.001), whereas androgen levels were not. A cluster analysis confirmed that there was a discrete subset of EM women with HA and metabolic abnormalities. CONCLUSIONS: HA is common in EM women and is associated with increased risks for MetS and dysglycemia. However, low SHBG levels rather than elevated androgen levels may be the primary predictor of this relationship with metabolic dysfunction.

Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated With Polycystic Ovarian Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer. OBJECTIVE: To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established. DESIGN: Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing. SETTING: Academic institution. PATIENTS: Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent. MAIN OUTCOME MEASURES: Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured. RESULTS: A method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids. CONCLUSIONS: A new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. OBJECTIVE: The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis. DESIGN, PATIENTS, AND METHODS: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. RESULTS: We found rare variants in DENND1A (P = 5.31 × 10-5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families. CONCLUSIONS: Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women With Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. OBJECTIVE: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. PARTICIPANTS/DESIGN: Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. RESULTS: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 × 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P < 1 × 10-9). CONCLUSION: The AMH signaling cascade plays an important role in PCOS etiology.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome.

Context: Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective: Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants: Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures: Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results: We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion: To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p23.1 [Corrected] and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

A retrospective, cross-sectional study reveals that women with CRSwNP have more severe disease than men.

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n = 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Genetic risk score for prediction of newborn adiposity and large-for-gestational-age birth.

CONTEXT: Macrosomic infants are at increased risk for adverse metabolic outcomes. Improving prediction of large-for-gestational-age (LGA) birth may help prevent these outcomes. OBJECTIVE: This study sought to determine whether genes associated with obesity-related traits in adults are associated with newborn size, and whether a genetic risk score (GRS) predicts LGA birth. SETTING AND DESIGN: Single nucleotide polymorphisms (SNPs) in 40 regions associated with adult obesity-related traits were tested for association with newborn size. GRS's for birth weight and sum of skinfolds (SSF) specific to ancestry were calculated using the most highly associated SNP for each ancestry in genomic regions with one or more SNPs associated with birth weight and/or SSF in at least one ancestry group or meta-analyses. PARTICIPANTS: Newborns from the Hyperglycemia Adverse Pregnancy Outcomes Study were studied (942 Afro-Caribbean, 1294 Northern European, 573 Mexican-American, and 1182 Thai). OUTCOME MEASURES: Birth weight >90th percentile (LGA) and newborn SSF >90th percentile were primary outcomes. RESULTS: After adjustment for ancestry, sex, gestational age at delivery, parity, maternal genotype, maternal smoking/alcohol intake, age, body mass index, height, blood pressure and glucose, 25 and 23 SNPs were associated (P < .001) with birth weight and newborn SSF, respectively. The GRS was highly associated with both phenotypes as continuous variables across all ancestries (P ≤ 1.6 × 10(-19)) and improved prediction of birth weight and SSF >90th percentile when added to a baseline model incorporating the covariates listed above. CONCLUSIONS: A GRS comprised of SNPs associated with adult obesity-related traits may provide an approach for predicting LGA birth and newborn adiposity beyond established risk factors.

Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a highly heritable complex trait. Parents of affected women have reproductive and metabolic phenotypes. OBJECTIVE: We tested the hypothesis that there are parental effects on the heritability of fasting dysglycemia in women with PCOS. DESIGN AND SETTING: This was a cross-sectional study at an academic medical center. PARTICIPANTS: PARTICIPANTS included 367 women with PCOS and their parents (1101 total subjects). MAIN OUTCOME MEASURES: We compared maternal and paternal contributions to heritability of fasting dysglycemia and to transmission of the PCOS susceptibility allele of D19S884 within the fibrillin-3 gene (D19S884-A8) on fasting dysglycemia. RESULTS: Fathers had higher fasting glucose levels, prevalence of fasting dysglycemia and proinsulin to insulin molar ratios (P < .0001), a marker of defective insulin processing, compared with mothers. Heritability of fasting dysglycemia was significant in PCOS families (h(2) = 37%, SE = 10%, P = .001). Maternal heritability (h(2) = 51%, SE = 15%, P = .0009) was higher than paternal heritability (h(2) = 23 %, SE = 23%, P = .186) of fasting dysglycemia after adjustment for age and body mass index. Within dysglycemic probands, there was increased maternal compared with paternal transmission of D19S884-A8 (maternal 84% vs paternal 45%, χ(2) = 6.51, P = .011). CONCLUSIONS: There was a sex difference in the parental metabolic phenotype with fathers having an increased risk of fasting dysglycemia and evidence for pancreatic ß-cell dysfunction compared with mothers. However, only maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 probands with fasting dysglycemia. These findings suggest that maternal factors, genetic and perhaps epigenetic, contribute to the metabolic phenotype in affected women.

The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome.

CONTEXT: Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear. OBJECTIVE: To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway. DESIGN: This was a case-control association study. SETTING: The setting was an academic medical center. PATIENTS OR PARTICIPANTS: A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS). INTERVENTIONS: Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels). MAIN OUTCOME MEASURES: The evidence for an association with PCOS and with 11 quantitative traits was investigated. RESULTS: Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing. CONCLUSIONS: Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

The role of TGF-ß in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic oligoanovulation and hyperandrogenism and associated with insulin resistance, type 2 diabetes, and cardiovascular risk. In recent years, genetic studies have linked PCOS to a dinucleotide marker D19S884 in the fibrillin 3 gene. Fibrillins make up the major component of microfibrils in the extracellular matrix (ECM) and interact with molecules in the ECM to regulate transforming growth factor ß (TGF-ß) signaling. Therefore, variations in fibrillin 3 and subsequent dysregulation of TGF-ß may contribute to the pathogenesis of PCOS. Here, we review the evidence from genetic studies supporting the role of TGF-ß in PCOS and describe how TGF-ß dysregulation may contribute to (1) the fetal origins of PCOS, (2) reproductive abnormalities in PCOS, and (3) cardiovascular and metabolic abnormalities in PCOS.