Functional Haplotypes of Human CD1D Gene

Qiaoyi Chen, MD, PhD, Principal Investigator
Natalie Jackson, BS
Postdoctoral Fellow
Postdoctoral Fellow

Abstract
CD1d is an MHC class I-like protein which can present lipid antigen to a conserved population of natural killer (NK) T cells. The NK T cells can produce large amounts of IL-4 and INF-? upon stimulation. Recent studies indicate that CD1d on T cells and intestinal epithelial cells can be up-regulated with INF-? or mitogens, and the levels of CD1d vary among individuals. This suggests that CD1d expression and its response to environmental stimulation may be associated with individual genetic variations. Unlike MHC class I or II genes, the coding region of CD1d gene is not polymorphic. It is thus possible that the regulatory region of the gene contributes to the individual variations. Understanding such genetic variations would be valuable for CD1d related functional studies.

We analyzed 21 reported single nucleotide polymorphisms (SNPs) in an approximately 4 kb 5´ upstream of exone-2 of the gene, and provide the evidence that SNPs can play a role in CD1d regulation. We then identified the promoter region and showed that the region contains enhancing and suppressing elements. We validated 12 SNPs, which are in complete linkage disequilibrium and comprise three haplotypes.

We hypothesize that the haplotypes can be grouped based on their functional effects on CD1d promoter activation and regulation. Accordingly, we propose in Specific Aim-1 to validate the remaining SNPs and to identify the genetic haplotypes in the 5´ upstream of CD1d gene. In Specific Aim-2, we propose to test the hypothesis that CD1d gene has distinctive 5´ upstream functional haplotypes. In Specific Aim-2, we propose to test the hypothesis that CD1d gene expression and regulation are associated with the distinctive functional haplotypes.

The identification of such functional haplotypes would allow for broad insights into the individual genetic variations and CD1d regulation. The completing of this project will reveal the characteristics of the CD1d gene promoter and the generated functional haplotypes can be used as specific markers for association studies, drug responses and stratification of individuals for NK T cell related functional studies or clinical trials.

Sponsor: NIH
Duration: 12/03 - 11/08