M. Brower

Further Investigation in Europeans of Susceptibility Variants for Polycystic Ovary Syndrome Discovered in Genome-Wide Association Studies of Chinese Individuals

CONTEXT Two genome-wide association studies (GWAS) of polycystic ovary syndrome (PCOS) have identified 11 susceptibility loci in Chinese individuals. Some of the risk loci identified in Chinese cohorts, mostly from the first GWAS, have been replicated in Europeans. Replication of the loci from the second GWAS in European cohorts is necessary to determine whether the same variants confer risk for PCOS in multiple ethnicities. OBJECTIVE The objective of the study was to determine the effects of the Chinese GWAS loci in European-origin individuals. DESIGN This was a genetic association study. SETTING The study was conducted at a tertiary care academic center. PATIENTS Eight hundred forty-five European subjects with PCOS and 845 controls participated in the study. INTERVENTIONS INTERVENTIONS included blood sampling and genotyping. MAIN OUTCOME MEASURE The association between PCOS and 12 independent single-nucleotide polymorphisms mapping to seven of the Chinese GWAS loci in a European cohort was measured. RESULTS Variants in DENND1A (P = .0002), THADA (P = .035), FSHR (P = .007), and INSR (P = .046) were associated with PCOS in Europeans. The genetic risk score, generated for each subject based on the total number of risk alleles, was associated with the diagnosis of PCOS (P < .0001) and remained associated (P = .02), even after exclusion of the four variants individually associated with PCOS. CONCLUSIONS At least four of the PCOS susceptibility loci identified in the Chinese GWAS are associated with PCOS in Europeans. The overall genetic burden for PCOS, as demonstrated by the risk score, is also associated with the diagnosis of PCOS in Europeans. The PCOS susceptibility loci identified in the Chinese GWAS are thus likely to play an important role in the etiology of PCOS across ethnicities.

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

The Severity of Menstrual Dysfunction as a Predictor of Insulin Resistance in PCOS

OBJECTIVE The objective of the study was to evaluate the relationship between the severity of menstrual disturbances and the degree of insulin resistance in women with polycystic ovary syndrome (PCOS). DESIGN This was a cross-sectional study. SETTING The study was conducted at a tertiary care academic medical center. PATIENTS Four hundred ninety-four women diagnosed with PCOS by the Rotterdam criteria and 138 eumenorrheic, nonhirsute, control women participated in the study. INTERVENTIONS INTERVENTIONS in the study included history and physical examination and blood sampling. MAIN OUTCOME MEASURE(S) Physical assessment and total and free T, dehydroepiandrosterone sulfate, fasting glucose, and insulin levels and calculated homeostatic model assessment values for insulin resistance (HOMA-IR) were measured. RESULTS Overall, 80% of PCOS subjects included had clinically evident oligomenorrhea. The remainder demonstrated vaginal bleeding intervals of fewer than 35 days (ie, with either polymenorrhea or clinically apparent eumenorrhea). Only 10% of PCOS subjects studied were ovulatory. After adjusting for body mass index, age, and race, all PCOS subjects with menstrual cycles longer than 35 days had significantly higher mean HOMA-IR levels than controls, and those with cycles longer than 3 months had the highest HOMA-IR levels. There was no difference in mean HOMA-IR levels between PCOS with regular vaginal bleeding (apparent eumenorrhea), regardless of whether they were anovulatory or not, or those with cycles fewer than 26 days, when compared with controls. CONCLUSIONS Women with PCOS and overt oligomenorrhea comprise the vast majority of PCOS subjects seen clinically and have significantly more insulin resistance than controls. About 20% of PCOS women seen reported vaginal bleeding intervals of fewer than 35 days in length and did not generally have overt insulin resistance, regardless of whether they were ovulatory or not. Overall, the presence of clinically evident menstrual dysfunction can be used to predict the presence and possibly the degree of insulin resistance in women with PCOS.

Analysis of Reported Adverse Events with Uterine Artery Embolization for Leiomyomas

STUDY OBJECTIVE To analyze and investigate reports associated with uterine artery embolization used for treatment of myomas using this database. DESIGN A retrospective review of the Manufacturer and User Facility Device Experience (MAUDE) database for events related to uterine artery embolization (Canadian Task Force Classification III). SETTING The MAUDE database was accessed online. PATIENTS Patients with myomas undergoing uterine artery embolization. INTERVENTIONS The MAUDE database was accessed online and searched for events related to uterine artery embolization reported between 1998 and 2018. These reports were reviewed and analyzed, reported events were categorized, and other relevant information was collected and tabulated. MEASUREMENTS AND MAIN RESULTS A total of 193 reports published during the study period were identified. Pain was the most frequently reported event (68 events; 35.2%), followed by vaginal discharge (45 events; 23.3%), operational misfire (37 events; 19.2%), and fever or infectious complications (36 events; 18.7%). A surgical procedure was required in 27 events (14.0%), with hysterectomy reported in 7.8% of the events. Death following this procedure was mentioned in 5 events (2.6%). CONCLUSION The MAUDE database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. A variety of adverse events associated with the use of uterine artery embolization were reported to the MAUDE database related to its use in the treatment of uterine myomas. We encourage physicians to review the MAUDE database when using medical devices, because this is an important tool to assess uncommon but major problems that could be associated with a medical device.