Dataset Information

Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS).

ABSTRACT: Polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women, is caused by both genes and environment. We and others previously reported association between single nucleotide polymorphisms (SNPs) in the DENND1A gene and PCOS. We therefore sequenced the DENND1A gene in white patients with PCOS to identify possible alterations that may be implicated in the PCOS pathogenesis. Patients were referred with PCOS and/or hirsutism between 1998 and 2011 (n = 261). PCOS was diagnosed according to the Rotterdam criteria (n = 165). Sequence analysis was performed in 10 patients with PCOS. Additional patients (n = 251) and healthy female controls (n = 248) were included for SNP genotyping. Patients underwent clinical examination including Ferriman-Gallwey score (FG-score), biochemical analyses and transvaginal ultrasound. Mutation analysis was carried out by bidirectional sequencing. SNP genotyping was tested by allelic discrimination in real-time PCR in the additional patients and controls. Sequencing of the DENND1A gene identified eight SNPs; seven were not known to be associated with any diseases. One missense SNP was detected (rs189947178, A/C), potentially altering the structural conformation of the DENND1A protein. SNP genotyping of rs189947178 showed significantly more carriers among patients with PCOS and moderate hirsutism compared to controls. However, due to small sample size and lack of multiple regression analysis supporting an association between rs189947178 and FG-score or PCOS diagnosis, this could be a false positive finding. In conclusion, sequence analysis of the DENND1A gene of patients with PCOS did not identify alterations that alone could be responsible for the PCOS pathogenesis, but a missense SNP (rs189947178) was identified in one patient and significantly more carriers of rs189947178 were found among patients with PCOS and moderate hirsutism vs. controls. Additional studies with independent cohort are needed to confirm this due to the small sample size of this study.

SUBMITTER: Eriksen MB

PROVIDER: S-EPMC3785455 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS).

Eriksen Mette B MB Nielsen Michael F B MF Brusgaard Klaus K Tan Qihua Q Andersen Marianne S MS Glintborg Dorte D Gaster Michael M

PloS one 20130927 9

Polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women, is caused by both genes and environment. We and others previously reported association between single nucleotide polymorphisms (SNPs) in the DENND1A gene and PCOS. We therefore sequenced the DENND1A gene in white patients with PCOS to identify possible alterations that may be implicated in the PCOS pathogenesis. Patients were referred with PCOS and/or hirsutism between 1998 and 2011 (n = 261). PCOS was ...[more]

PMID: 24086769

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Project description:PCOS is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below. NUgene project: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.

Project description:BackgroundThis study was undertaken to explore the treatment-seeking pathways traversed by women with PCOS and elicit their behavior, experiences and perspectives regarding it.MethodsThis concurrent mixed-method study was conducted on 18-40 years old women diagnosed with PCOS at the Gynecology outpatient department, PGIMER, Chandigarh, India. Of the 275 women, who were administered a questionnaire to elicit their treatment-seeking behavior, 62 willing participants were subjected to in-depth interviews. Quantitative responses were descriptively analyzed and presented as count, proportion, mean or median. Framework analysis was performed for the qualitative data. The findings of both types of data were triangulated to construct the pathways to treatment traversed by PCOS patients.FindingsMany (~45%) respondents had no information regarding PCOS. Only 9.1% received some information from their doctors. Though the internet was the primary source of information for 37.5% of respondents, they expressed dissatisfaction with the quality of information. Multiple health care agencies were consulted by most (85.8%) of the respondents. Allopathy was the preferred choice of treatment. The average delay in initiating the treatment was 3 months. The major reasons for this were ignorance, the concept of 'normality' and 'endurance'. Deviations from the normal self (like irregular-menstruation, obesity, hirsutism, infertility) were the concern that led them to consult a doctor. They were also dissatisfied with the treatment due to a late diagnosis, lack of relief, taboo, side-effects, expenses involved and the need for repeated laboratory tests. Participants' course of treatment was influenced by the interplay of individual, distress, health-system, and social-economic factors.ConclusionsWomen with PCOS were dissatisfied with the quality of the information and treatment received. There were treatment delays. The patients consulted multiple health agencies, including indigenous therapies, in the hope of relief. The findings provide an empirical basis on points to focus on for building better coping strategies for managing the condition.

Project description:ContextA genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.ObjectiveThe objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.DesignThis was a case-control study.SettingThe study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.PatientsCases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.InterventionThere were no interventions.Main outcomesMain outcomes were allele frequencies for seven variants in PCOS cases and controls.ResultsTwo strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.ConclusionsWe replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Dataset Information

Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS).

Publications

Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS).

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