Genomics and Epigenomics for New Insights in fEmale OAB (GENIE) Study
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Overactive Bladder, Endocrine |
| Therapuetic Areas: | Endocrinology, Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 11/11/2018 |
| Start Date: | May 1, 2017 |
| End Date: | January 18, 2020 |
Epigenomics in Insulin Resistance Associated Overactive Bladder.
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.
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.
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.
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.
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
We found this trial at
1
site
Durham, North Carolina 27710
(919) 684-8111
Principal Investigator: Nazema Y Siddiqui, MD
Phone: 919-401-1000
Duke University Younger than most other prestigious U.S. research universities, Duke University consistently ranks among...
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