Study of the Effect of Innate Immunity on the Inflammatory Response to Endotoxin
This research study will examine the role of innate immunity on the Inflammatory response of
monocytes and macrophages to endotoxin. A total of 559 healthy participants aged 18 years
and older will be identified and recruited from the Environmental Polymorphism Registry
(EPR). 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 controlled, observational gene association study will recruit participants on the basis
of genotype and then observe the phenotype of each participant. There are several SNPs of
interest in the genes TIRAP, MyD88, ABCA1, CD14, CD44, ITIH3, ITIH4, TLR4, and TNFa. In
addition there are alleles of interest in the gene ApoE. These alleles taken together are
considered a polymorphism. For each polymorphism of interest a separate group of
participants will be recruited (including heterozygous and homozygous for both the minor and
major alleles for each SNP). A maximum of 200 mLs of blood will be obtained from each
participant during one visit lasting approximately one hour. Blood monocytes will be
isolated from the donated blood samples and cultured to obtain macrophages. The macrophages
will be exposed ex vivo to an endotoxin (LPS) and to PAM3CSK4 to determine cell response
depending on genotype.
The primary objective is to determine associations between select polymorphisms in four
genes [TIRAP (TIR Associated Protein), MyD88 (Myeloid Differentiation Primary Response
Protein 88), ApoE (Apolipoprotein E), ABCA1 (ATP Binding Cassette Transporter A1, CD14,
CD44, ITIH3, ITIH4, TLR4, and TNFa] and quantitative in vitro inflammatory functions of two
cell types, the macrophage and neutrophil. The primary endpoints of this study for both
cell types will be levels of 6 cytokines - TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta
(ELISA) - induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS
We hope the results of this study may lead to discovery of important information regarding
the role of MDC1 (Mediator of DNA damage Checkpoint protein 1) in human disease, potentially
identifying new targets for future studies.
Michael B Fessler, M.D.
National Institute of Environmental Health Sciences (NIEHS)
United States: Federal Government
|NIEHS Clinical Research Unit (CRU)||Research Triangle Park, North Carolina|