The goal of the laboratory is to develop new approaches to the diagnosis and management of infectious complications in children with neoplastic diseases and HIV infection. A major effort of the laboratory has been to investigate genetic factors that contribute to disease susceptibility and outcome. To this end, we have investigated the influence of variant genotypes of molecules of innate immunity on disease susceptibility and outcome in immunocompromised patients. Under the stress of losing a major component of host defense (i.e., neutropenia or an absent respiratory burst), observed differences in phenotypic expression of disease might be related to polymorphisms in either a regulatory or structural region of primitive immune molecules, such as cytokines, Fc receptors, lectins and interleukins. We have taken the candidate gene approach, selecting known polymorphisms which influence either the level or functional activity of the molecule. In the process, we have created a database of known genetic single nucleotide polymorphisms (SNPs) in immunologically relevant genes in order to utilize existing SNPs for pathway-based association studies. The long-range goal of genetic association studies is to identify potential gentoypic differences that may bear important predictive value for infectious complications of disease (and perhaps other therapy related toxicities).We have also developed a series of collaborations with groups developing high-through-put SNP detection technologies. We have shown that variant genotypes of the myeloperoxidase, FCGR2A, FCGR3B genes have been associated with immunologically mediated complications of CGD. Rheumatologic conditions have been associated with variant genotypes of FCGR2A and MBL2. In addition, this study establishes a foundation for investigating other candidate loci in CGD; we have looked at genes that belong to specific pathways, such as the Th1/Th2 shift and chemokines, but found no evidence for a modifying gene effect. We have identified variant alleles of two genes, FCGR3A and IL6, each of which contributes to the development of Kaposi Sarcoma (KS) in HIV-infected men. The V allele of the FCGR3A gene is strongly associated with KS and influences the likelihood of developing infection with HHV-8, an important co-factor for KS. Further studies are underway to refine our understanding of the role FCGR3A and IL6 in the pathogenesis of KS in HIV infected men and in addition, those without HIV infection. We are currently conducting two large, international studies in cohorts with Wiskott-Aldrich Syndrome and Hyper IgM Syndrome. New initiatives are underway to investigate the contribution of SNPs to clinical outcomes in cohorts with cancer, HIV or a primary immunodeficiencies. Currently, we are investigating SNPs in parasitic diseases, ITP and cystic fibrosis. So far, our efforts have concentrated on the analysis of variant alleles of molecules of innate immunity; in particular, we have completed a preliminary analysis of a set of variant alleles in a large, healthy control population for the purpose of establishing a foundation for examining multiple SNPs. We have been able to look at the possible effect of immunologic SNPs on infection with herpes viruses. We have also concentrated on discovery of SNPs in molecules that belong to pathways critical to immune function and, more recently, cancer biology. This approach is critical for identifying possible genetic risk factors but also yields important observations that bear further in vitro analysis and lead to new insights in disease pathogenesis. For example, we have characterized common polymorphisms in c-MYC and shown the distribution varies according to the populations studied. A focus of the laboratory has also been to investigate the NADPH-oxidase, a multi-component enzyme system, primarily restricted to phagocytic cells. The NADPH-oxidase is responsible for the generation of oxygen radicals, critical to microbicidal and possibly, anti-tumor activity. Study of a rare, inherited disease, chronic granulomatous disease, in which patients are characterized by a defective NADPH-oxidase, has been especially useful for elucidating the regulation and assembly of the NADPH-oxidase complex. We have concentrated our efforts on characterizing the gene structures and regulation of three cytosolic components, p40-phox, p47-phox and p67-phox. Molecular analysis of p47-phox deficient autosomal recessive CGD patients has lead to a series observations detailing recombination events between the NCF1 gene and its highly homologous pseudogenes. Recently, we have conducted a search for common polymorphisms in all components of the NADPH-oxidase and have begun to systematically use these to look for SNPs that could modify outcome in immunocompromised hosts. AIDS RELATED 30%
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