Genomics and Epigenomics for New Insights in fEmale OAB (GENIE) Study

Completed

• Conditions: Overactive Bladder; Insulin Resistance

• Registration Number: NCT03057158
• Lead Sponsor: Duke University

Brief Summary

Millions of women suffer from overactive bladder, and the changes in bladder function affect their quality of life. The study team believes that it needs to be better understand why women get overactive bladder in the first place so that better treatments can eventually be offered.

The purpose of this study is to determine why women with insulin resistance are more likely to get overactive bladder. Overactive bladder is a type of bladder control problem that can cause some women to have bladder leakage. This problem is more common in women with diabetes and pre-diabetes, but it isn't known why.

Detailed Description

The methylation of cytosines in CpG sites can have profound effects on the ability of genes to be transcribed. To clarify and distinguish the specific methylation changes responsible for overactive bladder (OAB) in those with insulin resistance (IR), the investigator will compare three well-characterized groups of women: 1) OAB and IR; 2) IR only (no OAB); and 3) OAB only (no IR). In this proposal the investigator is only studying women since they are more likely to be affected by OAB with incontinence, the investigator wants to study pure cohorts of patients, and because this is the clinical population cared for by the primary investigator. The plan for future investigations is to apply these findings to broader groups to better understand gender and racial differences.

In Specific Aim 1, the investigator will conduct an epigenome-wide association study (EWAS) study, followed by targeted validation studies to determine whether CpG sites throughout the genome are differentially methylated in well-characterized and matched cohorts, while controlling for the effects of insulin-resistance. In Specific Aim 2, the investigator will assess for differential expression of candidate loci in relation to methylation. RNA-sequencing (RNA-seq) will be used to establish differences in the transcriptome between extreme phenotypes of OAB+IR and OAB alone. The investigator will then use quantitative polymerase chain reaction (qPCR) to validate expression differences in all cohorts, and to confirm differences in candidate loci that are confirmed in experiments from Aim 1. The investigator will proceed with bioinformatic pathway analyses to identify the function and interdependence of genes with altered expression and altered methylation profiles. In Specific Aim 3, the investigator will determine whether expression (mRNA and protein) differences in voided urine cells are also exhibited in biopsied bladder mucosa. The investigator will use targeted assays to confirm similar methylation profiles and gene expression in voided cells and bladder biopsies. The investigator will also compare protein expression of candidate loci such as EXOC6, ZFC3H1, RPS6KA2, and SPON2 proteins, if confirmed in other Aims, between cohorts. When the proposed studies have been completed, it is the expectation that the investigator will have functionally characterized the methylation changes that the investigator preliminarily identified in IR associated OAB.

Study Timeline

• Study First Submitted: 2017-02-13
• Study First Submitted QC: 2017-02-15
• Study First Posted: 2017-02-17
• Study Start: 2017-05-01
• Status Verified: 2019-11
• Primary Completion: 2020-03-09
• Study Completion: 2020-03-11
• Last Update Submitted: 2020-09-28
• Last Update Posted: 2020-09-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 257

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Proportions of differentially methylated CpG sites between cohorts, from Illumina EPIC chip	2 years	Extract DNA from voided urine cells and compare human DNA using Illumina EPIC Methylation Chip to assess methylation of different sites across the genome

Secondary Outcome Measures

Name	Time	Method
Compare methylation between DNA extracted from voided urine cells and bladder urothelial biopsies	2 years	DNA will be extracted from voided urine cells and from urothelial biopsies in the same patients. Targeted methylation assays will be used to compare methylation sites between sample types
Gene expression (from RNA-sequencing)	2 Years	Compare mRNA recovered from bladder biopsies between women in 3 cohorts (Urgency incontinence only, insulin resistance only, urgency incontinence with insulin resistance)
Gene expression (from PCR)	2 Years	Compare expression of candidate genes between cohorts by using polymerase chain reaction (PCR) and extracted RNA

Trial Locations

Locations (1)

Duke University; 🇺🇸 Durham, North Carolina, United States