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. For example, we have shown that variant genotypes of the myeloperoxidase, Fcgamma receptors 2a and 3b genes have been associated with immunologically mediated complications of CGD. Rheumatologic conditions have been associated with variant genotypes of FcR2a and MBL2. In addition, this study establishes a foundation for investigating other candidate loci in CGD. We have identified a novel genetic risk factor for developing Kaposi Sarcoma (KS) in HIV-infected men. The V allele of the Fcgamma RIIIa gene is strongly associated with KS and perhaps also 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 of FcgRIIIa and perhaps other loci, such as IL-6, which has been shown in a preliminary study to also confer risk for KS. New initiatives are underway that can readily be applied to other cohorts with cancer, HIV or a primary immunodeficiency in which the clinical endpoints are well characterized. We have also partenered with commercial approaches and published a proof-of- principle study, demonstrating the robustness and utility of a bio- electric chip assay for SNP characterization. We have also concentrated on analyzing variant alleles of at least twenty different molecules of innate immunity in a large, healthy control population. In an effort to begin to investigate multiple genetic variants within one or more immunologic pathways, we have investigated the distribution of variant gentoypes of that the low affinity Fcgamma receptors and established a foundation for future studies. 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. 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).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. Analysis of a cohort of patients with autosomal recessive CGD has been completed. We have also shown that NADPH-oxidase activity modulates the topoisomerase I mediated apoptosis pathway in neutrophils and human leukemia cell lines. AIDS RELATED 30% - Infection, NADPH-oxidase, Phagocyte, Genotype, Clinical association, - Human Subjects & Human Subjects: Minor under 18 Years Old
| Shen, Min; Vermeulen, Roel; Chapman, Robert S et al. (2008) A report of cytokine polymorphisms and COPD risk in Xuan Wei, China. Int J Hyg Environ Health 211:352-6 |
| Taylor 6th, James G; Ackah, Diana; Cobb, Crystal et al. (2008) Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease. Am J Hematol 83:6-14 |
| Garcia-Closas, Montserrat; Brinton, Louise A; Lissowska, Jolanta et al. (2007) Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study. BMC Cancer 7:60 |
| Savage, S A; Chanock, S J; Lissowska, J et al. (2007) Genetic variation in five genes important in telomere biology and risk for breast cancer. Br J Cancer 97:832-6 |
| Easton, Douglas F; Pooley, Karen A; Dunning, Alison M et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087-93 |
| Peters, Ulrike; Foster, Charles B; Chatterjee, Nilanjan et al. (2007) Serum selenium and risk of prostate cancer-a nested case-control study. Am J Clin Nutr 85:209-17 |
| Purdue, Mark P; Hartge, Patricia; Davis, Scott et al. (2007) Sun exposure, vitamin D receptor gene polymorphisms and risk of non-Hodgkin lymphoma. Cancer Causes Control 18:989-99 |
| Haiman, Christopher A; Dossus, Laure; Setiawan, V Wendy et al. (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67:1893-7 |
| NCI-NHGRI Working Group on Replication in Association Studies; Chanock, Stephen J; Manolio, Teri et al. (2007) Replicating genotype-phenotype associations. Nature 447:655-60 |
| Cox, Angela; Dunning, Alison M; Garcia-Closas, Montserrat et al. (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352-8 |
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