Dr. Janardan P. Pandey
Dept. of Microbiology and Immunology
Med. Univ. of SC
173 Ashley Ave.
Charleston, SC 29425
Phone: 843 792 4360
Fax: 843 792 2464
E-mail: pandeyj@musc.edu
Number of Human Subjects projects reported: 1
| MUSCBP-95-6241 | "Trichloroethylene Exposure and Host Genetic Factors in Autoimmune Diseases" |
"Trichloroethylene Exposure and Host Genetic Factors in Autoimmune Diseases"
Principal Investigator: Dr. Janardan P. Pandey, Medical University of South Carolina, Environmental Biosciences Program
Project started in: 1995
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Medical University of South Carolina, Environmental Biosciences Program
Most recent approval: 12/06/02
IRB approval number: 6241
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 355
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
The overall long-term goal of this project is to identify the genetic and environmental factors that contribute to the pathways to autoimmunity. In particular, we would like to determine how certain genes of the immune system and those involved in the bioactivation of particular environmental toxicants interact in causing autoimmune diseases. We also plan to develop a murine model for use in dissecting the biological mechanisms underlying environmentally associated autoimmunity. Specifically, we would like to determine whether the exposure of mice to trichloroethylene (TCE) causes activation of microchimeric cells and the appearance of dermal inflammation and fibrosis similar to that of graft-versus-host disease, a condition with remarkable similarities to systemic sclerosis (SSc). The proposed study will address the following specific aims:
Specific Aim 1: (a) To further estimate the magnitude of the association between TCE/silica exposure and SSc, SLE, and myositis and (b) to determine if the effect is modified by the prevalence of disease-specific autoantibodies — anti-topoisomerase I, anticentromere, and anti-RNA polymerase I and III in SSc; anti-Sm in patients with SLE; and anti-tRNA synthetases in myositis.
Specific Aim 2: To compare the distribution of particular genetic markers (HLA, TNF-_, TNF-____IL-1_, IL-1RA, IL-10, CTLA-4__DNASE1, cytochrome P450IIE1, GM, and KM) and the recently-identified SNPs closely linked to them, among TCE/silica exposed SSc, SLE, and myositis patients with (a) non-exposed patients and (b) non-autoimmune controls.
Specific Aim 3: To compare the association of autoantibodies with the immunogenetic markers among TCE/silica-exposed and nonexposed SSc, SLE, and myositis patients.
Specific Aim 4: To develop a murine model for use in examining the role of microchimeric cells and TCE exposure in SSc pathogenesis.
Specific Aim 5: To construct transgenic mice with different combinations of CTLA-4 genotypes and expose them to TCE to determine the possible interactive effects of CTLA-4 alleles and TCE exposure in producing dermal inflammation and fibrosis.
Data on occupational histories will be obtained by personal interviews. Job exposure matrices and an adapted version of expert assessment methods will be used to quantify occupational exposure to TCE and silica, respectively. HLA-DQ and DR alleles will be typed by the PCR-SSP (sequence-specific primers) method. The DP alleles will be determined by the PCR-RFLP (restriction fragment length polymorphism) technique described previously. Samples will be typed for TNF-_, TNF-_, IL-10, and IL-1_ bi-allelic RFLPs, using PCR-based methods described elsewhere. Genotypes of penta-allelic IL-1RA polymorphism will be determined as described by Tarlow et al. Three polymorphic sites in the cytochrome P450IIE gene—RsaI/PsaI site in the 5' flanking region, the Dra I site in intron 6, and the Taq I site in intron 7—will be studied using the primers and PCR conditions described previously. Genotypes of CTLA-4 and DNASE1 will be determined by recently-described methods. Disease-specific autoantibodies will be measured by established ELISA methods. SNPs will be detected by DNA sequencing methods. Logistic regression, log-linear analyses, chi-square, and Fisher’s two-tailed exact tests will be used to analyze the data, employing the Statistical Analysis Software (SAS Institute Inc., Cary, NC). All analyses will be ethnically stratified.
Following informed consent, subjects (all adults) are interviewed about their residential, occupational, and medical histories and 15 ml of blood is drawn from a vein in the arm during a single visit. Blood is used for determining autoantibodies and genetic markers. There is no subsequent contact with the subjects and they are not informed of the results of the study. Blood drawing (venipuncture) involves following risks: (1) There may be a slight pain when the arm is stuck with the needle; (2) A bruise may be left temporarily at the spot where the arm is stuck; and (3) There is a slight risk of inflammation of the vein and/or blood clot formation, although this is extremely rare. No direct benefit to the subjects is expected. In general, the results of these studies may benefit medical science by elucidating the role of immunogenetic markers and organic solvents exposure in autoimmune diseases.
Participant's records of participation in this study are not accessible to the general public and every effort is made to maintain confidentiality. However, all records in South Carolina may be subject to subpoena by a court of law. Information gained from this study is used only for research and educational purposes. Information is published in medical journals, but the participant's identity is not revealed. However, identifying information will be available to monitors from the MUSC IRB for Human Research and the U.S. Food and Drug Administration.