The human leukocyte antigen (HLA) complex encodes multiple highly polymorphic molecules that are central to immune function. Certain of these molecules act as ligands for the equally polymorphic killer cell immunoglobulin-like receptors (KIR). Specific alleles as well as compound genotypes from the HLA and KIR genomic regions have been implicated in susceptibility or resistance to infectious, allergic, inflammatory, and autoimmune diseases, as well as to outcomes of hematopoietic cell transplantation and reproductive success. For many of these associations it has been difficult to identify the causative alleles, due to the complexity of these genomic regions. Previous studies isolating causative mutations required multiple approaches and lengthy procedures. In contrast, we have developed a high-throughput, cost-effective method that allows us to capture and sequence the complete haplotypes of both the HLA (4.8 Mb) and KIR (100-250 kb) regions. We will employ this method in Aim 1 to study dermatomyositis (DM), an autoimmune idiopathic myopathy. DM has a well-defined, poorly-understood, association with HLA. Implicating KIR involvement are changes in HLA class I expression in diseased tissue and the contribution of innate immunity to the disease process. Specific clinical phenotypes track with the presence of specific autoantibodies. We will obtain complete HLA and KIR haplotype sequences from patients in each of the major clinical groups and compare them to those from healthy HLA-matched controls. Comparisons will be made within and between groups to identify individual markers or compound genotypes that cause or exacerbate disease.
In Aim 2 we will examine the association of HLA and KIR polymorphism with preeclampsia, a systemic hypertensive condition of pregnancy and a leading cause of maternal mortality, particularly in women of African origin; in the US, African-American women are up to five times more likely to suffer from preeclampsia. A cohort of African women and their babies will be analyzed, complementing our study of European women undertaken in the current round of funding. Low- resolution analysis of the African cohort has replicated the finding observed in the European cohort, namely that highest risk for preeclampsia is in pregnancies where the mother has two copies of the KIR A haplotype and the fetus has inherited the C2 ligand from the father. In contrast to the European cohort, where KIR2DS1 is protective, in the African cohort protection is associated with centromeric KIR2DS5, a gene unique to African populations. Unknown is whether polymorphism at the centromeric KIR2DS5 gene in the African populations affords functional replacement for the lack of KIR2DS1. Other linked and functionally interacting loci that may contribute to reproductive success are HLA-G in the HLA region and KIR2DL4 in the KIR region. By obtaining complete sequence for the HLA and KIR haplotypes in the preeclampsia and control cohorts we will be able to assess the contribution of both individual and compound features to disease outcome.
Aims 3 and 4 will continue to improve and extend the bioinformatic (Aim 3) and technical (Aim 4) components of our method.
The human leukocyte antigen (HLA) complex and the killer cell immunoglobulin-like receptor (KIR) gene family are functionally interacting genomic regions associated with a wide range of human infectious and autoimmune diseases, as well as reproductive success and the outcome of therapeutic transplantation. In this project we will investigate dermatomyositis, a life-threatening and debilitating autoimmune disease, and preeclampsia, a disease of pregnancy with significant morbidity and mortality worldwide, especially for women of African origin.
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