Abstract
Disclosure: C. Parker: None. R. Bauer: None. C.K. Welt: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None.
Background: Polycystic ovary syndrome (PCOS) is a multisystem endocrine ...disorder and is the most common form of anovulatory infertility of reproductive aged women (6-15%). PCOS is characterized by the presence of hyperandrogenemia, irregular menses, and polycystic ovarian morphology. A previous twin study has shown PCOS to be highly heritable (h2=0.72). Thus, we hypothesize that genetic variation is a major contributor to the etiology of PCOS. Objective: Our goal is to identify the genetic factors that contribute to the PCOS phenotype and how they define phenotypic subtypes of PCOS with the aim of better understanding PCOS pathology and optimizing treatment strategies for individual women. Methodology: We are performing whole exome sequencing (WES) supplemented with genomic regions mapping to PCOS GWAS loci on 772 subjects with PCOS and 300 age and ancestry-matched controls to generate a comprehensive catalog of PCOS-associated protein coding variants. We will use prediction tools to identify likely-to-be deleterious variants and in silico evidence of epigenetic modification to identify PCOS associated genes/pathways. We will then prioritize variants for molecular follow-up creating a comprehensive catalog of protein coding variants associated with PCOS. We expect the variants identified by WES to map to multiple genes and pathways including novel genes/pathways which have not previously been implicated in PCOS as well as genes/pathways that have previously been shown or predicted to play a major role in the etiology of PCOS by us or other groups. Results: To date we have obtained high quality sequencing data on 772 women with PCOS. Sequencing of 300 age and ancestry matched reproductively heathy women is being started. We have identified 81 rare protein coding genetic variants using targeted re-sequencing in three distinct pathways in an independent PCOS cohort. These genes are associated with insulin resistance, the gonadotropin signaling pathway and the Anti-Müllerian Hormone (AMH) signaling pathway. We identified 37 functionally validated deleterious variants in genes that encode AMH or its cognate receptor AMHR2, 7 rare variants that encode LMNA, 11 rare (MAF <0.1) variants that encode the insulin receptor, and 26 coding variants for the genes encoding the beta subunit of gonadotropins, LH and FSH, and their receptors, FSHR and LHCGR. Conclusion: We have identified 81 rare protein altering genetic variants in pathways that are predicted to be impaired in individuals with PCOS supporting a critical role for genetics in the etiology of PCOS. Our WES screen will allow us to generate a comprehensive catalog of likely to be deleterious PCOS associated variants. This catalog of variants will identify the genes/pathways that are mutated in PCOS leading to improved personalized phenotyping and treatment of PCOS.
Presentation Date: Friday, June 16, 2023
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.
LATTICE is a first-of-its-kind micro- to millifluidic tissue-agnostic platform able to recreate
para
- and endocrine signaling
in vitro
.
Context and Objective: Of the recently identified type 2 diabetes mellitus (T2D) susceptibility loci, transcription factor 7-like 2 (TCF7L2) confers the greatest relative risk for T2D and ...significantly predicts conversion to T2D in persons with impaired glucose tolerance. TCF7L2 is, therefore, also a strong candidate gene for polycystic ovary syndrome (PCOS), a common endocrine disorder characterized by androgen excess and menstrual irregularities and associated with insulin resistance and a 7-fold increased risk for T2D.
Research Design and Methods: We tested for association between 58 single nucleotide polymorphisms mapping to TCF7L2 and PCOS in 624 index (PCOS) cases and 553 control women of European ancestry. Furthermore, in the women with PCOS, we tested for association with seven reproductive and metabolic quantitative traits.
Results: Although we did not detect evidence for association between the previously described TCF7L2 T2D locus, the proinsulin:insulin molar ratio, a marker of pancreatic β-cell dysfunction, was strongly associated with this locus (P = 2.1 × 10−4). We also observed evidence for association between PCOS and two single nucleotide polymorphisms, rs11196236 (P = 9.0 × 10−4) and rs11196229 (P = 0.0027) mapping more than 100 kb centromeric to the previously published T2D susceptibility loci.
Conclusions: We have observed evidence of association with two independent TCF7L2 loci in a PCOS cohort: 1) association between the proinsulin:insulin molar ratio and the T2D locus; and 2) association with reproductive PCOS phenotype and a novel locus. This study suggests that variation in different regions of a susceptibility gene contributes to distinct phenotypes.
Two independent TCF7L2 loci are associated with glucose tolerance in women with PCOS and with PCOS, respectively.
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.
Persistence Pays Off for PCOS Gene Prospectors Strauss, Jerome F; McAllister, Jan M; Urbanek, Margrit
The journal of clinical endocrinology and metabolism,
7/2012, Letnik:
97, Številka:
7
Journal Article
Abstract
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.
Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences ...between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.
The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m
). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10
) and rs2228260 within XBP1 (P = 3.68 × 10
). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10
). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10
) and a gene-based association was identified with ERBB4 (P = 1.59 × 10
). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.
Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.
Context: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant ...association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.
Objective: The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations.
Design: The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS.
Setting: The study was conducted at academic medical centers.
Patients or Other Participants: A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS.
Intervention(s): There were no interventions.
Main Outcome Measure(s): The outcome measure was transmission frequency of SNP alleles.
Results: We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT χ2 = 10.0 (P = 0.0016) and haplotype-C/A8 TDT χ2 = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, χ2 = 9.1; Pcorrected = 0.042) is significant after correction for multiple testing.
Conclusions: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.
Family-based transmission disequilibrium test analysis provides evidence for genetic association between PCOS and polymorphic variants in two genes, FBN3 and POMC.
Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from oral glucose ...tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy.
We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics.
The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCF7L2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08).
Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants.
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