Study of the Effect of SNPs in p53 and p53 Response Elements on the Inflammatory Response to DNA Damage
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|ClinicalTrials.gov Identifier: NCT01143519|
Recruitment Status : Enrolling by invitation
First Posted : June 14, 2010
Last Update Posted : June 20, 2018
|First Submitted Date||June 11, 2010|
|First Posted Date||June 14, 2010|
|Last Update Posted Date||June 20, 2018|
|Study Start Date||May 24, 2010|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures||Not Provided|
|Original Primary Outcome Measures||Not Provided|
|Change History||Complete list of historical versions of study NCT01143519 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures||Not Provided|
|Original Secondary Outcome Measures||Not Provided|
|Current Other Outcome Measures||Not Provided|
|Original Other Outcome Measures||Not Provided|
|Brief Title||Study of the Effect of SNPs in p53 and p53 Response Elements on the Inflammatory Response to DNA Damage|
|Official Title||Effect of SNPs in p53 and p53 Response Elements on the Inflammatory Response to DNA Damage|
- Research has shown that certain proteins in cells may be linked to higher risks of developing inflammations, tumors, and other medical problems. By examining how the blood cells of healthy volunteers respond to environmental exposures, researchers hope to better understand the relationship of genes, environmental factors, and human diseases.
- To examine how specific genes and proteins in blood cells respond to environmental exposures.
- Healthy volunteers between 18 and 45 years of age.
This research study will investigate the role of SNPs in p53 and p53 response elements on the inflammatory response to DNA damage. A total of 200 participants aged 18 years and older carrying one of the five SNPs of interest and wild-type controls will be identified and recruited from the Environmental Polymorphism Registry (EPR). In addition, participants will be recruited based on their health outcomes and SNP associations from the EPR registry to study genotype-phenotype effects on lymphocytes. The EPR is a long-term project to collect and store up to 15,000 DNA samples for use in research studies from individuals in the greater North Carolina Triangle Region.
This observational gene association study will recruit participants on the basis of genotype or phenotype and then observe the lymphocyte response to chemotherapeutic agents and relevant environmental pathogens. The SNPs of interest are p53, as well as four of its downstream target genes including FLT1, MDM2, TLR8 and RRM1. A maximum of 320 mLs of blood will be obtained from each participant during one visit lasting approximately one hour. Cells from the donated blood samples will be examined for their response to exposed environmental stress ex vivo.
The primary objective is to determine the association between five SNPs and p53 target gene expression after exposure to Nutlin or doxorubicin (chemotherapeutic agents) with outcome measured by RT-PCR. The five SNPs are p53 rs1042522, MDM2 rs2279744, FLT1 C-677T, TLR8 rs3761624 and RMM1 rs1465952. The secondary objectives are to: (1) to determine the p53 promoter occupancy measured by ChIP analysis for the following SNPs: FLT1 C-677T, TLR8 rs3761624 and RMM1 rs1465952; (2) to measure apoptosis by Annexin V-PI assay for p53 rs1042522 SNPs; (3) to examine the cell cycle profile analysis (FACS) by cytofluorometry for p53 rs1042522SNPs; and (4) to determine DNA repair using Pulse Field Electrophoresis Gel (TAFE gels) for the following p53 rs1042522SNPs. Furthermore, the association between the SNPs of interest and phenotypic characteristics will be explored using the EPR health and exposure survey to identify significant genotype-phenotype associations in the EPR population. The effect of the associations will be tested on lymphocyte function after exposure to Nutlin or doxorubicin.
We have established that p53 can greatly alter expression of many immune genes including most of the toll-like receptor (TLR) innate immunity genes which are considered important components of antiviral immunity against HIV infection. Given the unique roles of TLR signaling during acute HIV-1 infection and their potential role in chronic inflammation, it is important to elucidate whether TLR polymorphisms contribute to HIV-1 pathogenesis and variability in disease progression.
Recently, we confirmed that p53 can target the TLR8 ssRNA responsive receptor in a single nucleotide polymorphism (SNP)-dependent manner (rs3761624). We have shown in a human study that a SNP within a p53 response element of the TLR8 promoter can strongly influence respiratory syncytial virus (RSV)-associated disease in infants. In addition, there are SNPs in the coding region of p53 that alter the amplitude of signaling attributed to this protein. Projecting these findings to HIV and AIDS, we hypothesize that p53 is a downstream effector that initiates anti-proliferative innate immune responses to viruses and other pathogens, establishing a new role for p53. These novel investigations will provide critical understanding of the role of innate restriction factors in resistance to HIV-1 and disease progression.
Overall, we hope the results of this study lead to discovery of important information regarding the role of SNPs located in p53 and p53 response elements in human disease, potentially identifying new targets for future studies.
|Study Design||Time Perspective: Other|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Study Groups/Cohorts||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status||Enrolling by invitation|
|Original Estimated Enrollment
|Study Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
All positive HIV, hepatitis B, and hepatitis C results that are unexpected (i.e. participant is not currently enrolled in the EPR as an HIV-1 seropositive under medicament treatment) will be promptly communicated to the donor by the study doctor/PI or the CRU Director. The participant will be referred to their physician and/or to the N.C. Department of Health for confirmatory testing and counseling. As explained in detail in the attached Supplement describing N.C. State Department of Health code will be followed. The state code mandates reporting of positive results along with the participant s name and identifying information to the N.C. Department of Public Health. Upon contracting with the testing laboratory, clarification will be obtained and documented as to whether the contracted laboratory or the study MD will be responsible for reporting positive results to the state to avoid duplication of reporting. Upon receipt of the test results, the N.C. Department of Health will contact the participant to inform them of the positive result, how to find care, how to avoid infecting others, how the newly diagnosed HIV and/or hepatitis infection is reported, and the importance of informing their partners at possible risk because of their HIV and/or hepatitis infection. If the HIV, hepatitis B, and hepatitis C results are negative, the participant will be not be notified. However, the participant may contact the research study nurse for their results. HIV and hepatitis B/C test results, non-reactive and reactive, will be documented confidentially by the PI or study coordinator in the subject s file, and kept in a locked file
cabinet in the CRU Medical Records Room. In order to document the reporting procedure and the time associated with the reporting process, a document has been created and placed in the study specific manual (Hepatitis B/C and HIV Notification Process for Reactive Results Form).
-Healthy control participants carrying SNPs TLR8 and FLT1 who are currently taking hormonal contraception (e.g. oral contraceptives, IUDs with hormones, contraceptive patches) or hormone replacement therapy will be excluded from the study unless the participant has been off of the hormone treatment for 1 month or longer.
|Ages||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers||Yes|
|Contacts||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries||United States|
|Removed Location Countries|
|Other Study ID Numbers||100134
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )|
|Study Sponsor||National Institute of Environmental Health Sciences (NIEHS)|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||April 27, 2018|