KIR2DL4 variability and haplotypes in a Brazilian population sample from the State of São Paulo.

Abstract

The human immune system presents a complex mechanism responsible for the regulation of immune responses by different cellular and biochemical pathways. The first line of defense is played by Natural Killer cells (NK). Through the Human Killer-cell Immunoglobulin-like Receptors (KIRs), NK cells bind to HLA class I molecules present in the target cell surface. When NK are unable to recognize those HLA class I molecules, they induce cell death. Together, theses complex receptors are key features for controlling and modulating immune responses. Polymorphisms in KIR genes might disrupt the KIR/HLA binding, or even influence KIR expression. However, KIR variability is not well explored, mainly in admixed populations such as Brazilian, although many of the KIR genes, such as KID2DL4, are related to many pathological conditions such as recurrent abortion and preeclampsia. Here we propose to evaluate KIR2DL4 variability on an urban population sample from the State of São Paulo (Southeaster Brazil), which is characterized by high inter-ethnic admixture and is considered a large repository of genetic variation. We have previously characterized HLA class I genes variability in the same sample that will be processed for KIR2DL4. The complete segment encompassing the KIR2DL4 gene (promoter, all exons, all introns and the entire 3' untranslated region) will be evaluated by using massively parallel sequencing (or Next Generation Sequencing - NGS) procedures. The KIR2DL4 variability and haplotype data will be correlated with the HLA class I variability (mainly HLA-G, the most important ligand to KIR2DL4). In addition, KIR2DL4 variability and haplotypes will be used to infer signatures of natural selection acting on the coding and regulatory sequences and to infer a panel of microRNAs that may influence its expression, as well as to detect functional polymorphic sites in the coding and regulatory regions. This data will lead to a better understanding of the expression regulation of KIR genes and will allow a future development of expression manipulation strategies for therapeutic use. (AU)