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

• ClinicalTrials.gov Identifier: NCT03057158
• Recruitment Status: Completed
• First Posted: February 17, 2017
• Last Update Posted: September 29, 2020
• Sponsor: Duke University
• Information provided by (Responsible Party): Duke University

Study Description

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.

Condition or disease
Overactive Bladder; Insulin Resistance

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 Design

• Study Type: Observational
• Actual Enrollment: 257 participants
• Observational Model: Other
• Time Perspective: Prospective
• Official Title: Epigenomics in Insulin Resistance Associated Overactive Bladder.
• Actual Study Start Date: May 1, 2017
• Actual Primary Completion Date: March 9, 2020
• Actual Study Completion Date: March 11, 2020

Groups and Cohorts

Group/Cohort
1; Women with Urgency Incontinence (At least three times per week) greater than three months, and without insulin resistance.
2; Women with insulin resistance (pre-diabetes or diabetes based on Hemoglobin A1C).
3; Women with both UUI (at least three times per week for over three months) and Insulin Resistance (pre-diabetes or diabetes based on Hemoglobin A1C).
4; Healthy Volunteers

Outcome Measures

Primary Outcome Measures :

1. Proportions of differentially methylated CpG sites between cohorts, from Illumina EPIC chip [ Time Frame: 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 :

1. Compare methylation between DNA extracted from voided urine cells and bladder urothelial biopsies [ Time Frame: 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
2. Gene expression (from RNA-sequencing) [ Time Frame: 2 Years ]
   Compare mRNA recovered from bladder biopsies between women in 3 cohorts (Urgency incontinence only, insulin resistance only, urgency incontinence with insulin resistance)
3. Gene expression (from PCR) [ Time Frame: 2 Years ]
   Compare expression of candidate genes between cohorts by using polymerase chain reaction (PCR) and extracted RNA

Biospecimen Retention:   Samples With DNA

Urine and blood samples.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

We will recruit of a total of 450 women from three groups (at least 130 women in each cohort: 1) OAB and IR; 2) IR only; and 3) OAB only) to provide limited clinical information, blood, and urine samples. A subset of these participants (20 from each group, or 60 total) will be further recruited to provide non-muscle invasive (urothelium only) bladder biopsies. Women will be recruited through advertising and from clinical sites at Duke University Health System.

Criteria

Inclusion criteria:

• Women over the age of 18.
• Urgency incontinence (at least 3 times per week) for > 3months
• History of elevated A1C or Type II diabetes (UUI+IR and IR only groups)
• Non-pregnant
• At least 6 months since most recent childbirth

Exclusion criteria:

• Active pregnancy, or within 6 months of childbirth
• Breastfeeding
• Proteinuria (defined as >1+ protein on urine dipstick in the absence of infection)
• Gross hematuria (in the absence of UTI)
• Type I diabetes mellitus
• Type II diabetes with chronic renal impairment (Cr >1.5)
• Chronic renal disease (includes vasculitis, focal segmental glomerulosclerosis, lupus nephritis, polycystic kidney disease, nephropathy)
• Receiving chemotherapy or radiation for malignancy
• Taking one of the following drugs that influence DNA methylation: hydralazine, procainamide, methotrexate, valproic acid, tamoxifen, raloxifene, letrozole, anastrozole (Arimidex), or exemestane (Aromasin)
• Any history of urinary tract malignancy (bladder, urethra, ureter, kidney)
• Intradetrusor Botox injection within the prior 12 months

Contacts and Locations

Locations

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27707

Sponsors and Collaborators

Duke University

Investigators

• Principal Investigator: Nazema Y Siddiqui, MD; Duke University

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT03057158
• Other Study ID Numbers: Pro00079255; 302-0870 ( Other Grant/Funding Number: NIDDK )
• First Posted: February 17, 2017
• Last Update Posted: September 29, 2020
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Duke University:

OAB; Insulin resistance; diabetes; pre-diabetes

Additional relevant MeSH terms:

Urinary Bladder, Overactive; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Urinary Bladder Diseases; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations