Biography:

Dr. Winkler received her graduate degree in Immunogenetics from the University of Maryland, College Park in 1986 and has spent her professional career at the National Cancer Institute investigating the role of host genetic variation in infectious diseases and other complex diseases. She is a Principal Investigator in the Laboratory of Genomic Diversity and is a Principal Investigator or a member of the executive boards of three multicenter studies:  The Hemophilia Growth and Development Study, the Hemophilia Genetics Inhibitor Study, and the Family Investigation of Nephropathy and Diabetes.

Research:

The major objectives of my laboratory group are to identify host factors that contribute to infectious and other complex diseases with the goals of identifying targets for therapeutic intervention, improving diagnosis, and informing interpretation of clinical and vaccine trials.

1. Identification of genetic susceptibility/restriction factors to HIV-1, HCV and HBV infection and disease progression
   Host factors contribute to individual susceptibility to infection, clearance and pathogenesis of viral infections including HIV-1, HCV and HBV. We have recently focused on four major groups of genes for their role in viral infection and pathogenesis. These include genes involved in: 1) the innate immunity pathways that target HIV-1 or other viral pathogens; 2) cytokines that regulate immune response; 3) host factors involved in successful completion of the viral life cycle; and 4) chemokine receptors that provide portals for HIV-1 cell entry and chemokines that bind these receptors.
2. Genetic investigation of nasal pharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC)
   NPC and HCC are multifactoral cancers that are caused by interactions among genetic, virologic and environmental factors. NPC and HCC are associated with dietary and environmental risk factors and chronic infection by Epstein-Barr Virus (EBV) or by Hepatitis B Virus, respectively. Both cancers have unusually high prevalence rates in southeast China, where the risk of exposure to dietary risk factors is extremely high. We are investigating the effects of host genetic factors and their interactions on NPC and HCC susceptibility in participants from Guangxi and Guangdong Province of Southern China.
3. Identification of genetic factors in kidney disease
   Focal segmental glomerulosclerosis (FSGS) is the leading cause of primary nephrotic syndrome in adults and the leading cause of end-stage renal disease in children. Together with Dr. Jeffrey Kopp, NIDDK, we have accrued over 1200 FSGS cases and normal and hypernormal controls. We are also participating in the Family Investigation of Nephropathy and Diabetes (FIND) consortium, with the goal of discovering genetic risk factors for diabetic nephropathy and end stage renal disease.
4. Identify genetic factors contribute to the development of inhibitors to factor VIII.
   Antibodies (inhibitors) to Factor VIII inhibitor develop in approximately 30% of persons with hemophilia A and greatly increases the difficulty of managing hemophilia. We are participating in an international collaboration, HIGS (Hemophilia Genetics Inhibitor Study), to identify genes that contribute to the development of inhibitors in persons with hemophilia A. This study is using a combination of family and association studies to identify genetic and environmental risk factors and their interactions that may be risk predictors.

Publications:

Winkler, C.A., Modi, W., Smith, M.W., Nelson, G.W., Wu, X., Carrington, M., Dean, M., Honjo, T., Tashiro, K., Yabe, D., Buchbinder, S., Vittinghoff, E., Goedert, J.J., O'Brien, T.R., Jacobson, L.P., Detels, R., Donfield, S., Willoughby, A., Gomperts, E., Vlahov, D., Phair, J., ALIVE, HGDS, MACS, MHCS, SFCC, and O'Brien, S.J. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 279: 389-393, 1998.

Daar, E.S., Lynn, H., Donfield, S., Gomperts, E., Hilgartner, M.W., Hoots, W.K., Chernoff, D., Arkin, S., Wong, W.-Y., Winkler, C.A., and the Hemophilia Growth and Development Study. HCV viral load is associated with human immunodeficiency virus disease progression in hemophiliacs. J Infect Dis 183: 589-595, 2001. [ PDF ]

An, P. Nelson, G.W., Wang, L., Donfield, S., Goedert, J.J., Phair, J., Vlahov, D., Buchbinder, S., Farrar, W., Modi, W., O'Brien, S.J., and Winkler, C.A . Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc Natl Acad Sci USA 99: 10002-10007, 2002. [ PDF ]

An, P., Bleiber, G., Duggal, P., Nelson, G.W., May, M., Mangeat, B., Alobwede, I., Trono, T., Vlahov, D., Donfield, S., Goedert, J.J., Phair, J., Buchbinder, S., O'Brien, S.J., and Winkler, C.A. APOBEC3G genetic variants and their influence on AIDS. J Virol 78: 11070-11076, 2004. [ PDF ]

Berntorp, E., Astermark, J., Donfield, S.M., Nelson, G.W., Oldenburg, J., Shapiro, A.D., DiMichele, D.M., Ewenstein, B.M., Gomperts, E.D., and Winkler, C.A. for the Hemophilia Inhibitor Genetics Study. Hemophilia Inhibitor Genetics Study (HIGS)-evaluation of a model for studies of complex diseases using linkage and association methods. Hemophilia 11: 427-429, 2005.

Daar, E.S., Lynn, H., Donfield, S., Lail, A., O'Brien, S.J., Huang, W., and Winkler, C.A. for the Hemophilia Growth and Development Study. Stromal cell-derived factor-1 genotype, co-receptor tropism and human immunodeficiency virus type 1 progression. J Infect Dis 192: 1597-1605, 2005.

Franceshini, N., North, K.E., Kopp, J.B., McKenzie, L., and Winkler, C.A. NPHS2 gene, nephritic syndrom and focal segmental glomerulosclerosis: a HuGE review. Genet Med 8: 63-75, 2006.

Modi, W., Lautenberger, J., An, P., Scott, K., Goedert, J., Kurt, G.D., Buchbinder, S., Phair, J., Donfield, S., O'Brien, S.J., and Winkler, C.A . Genetic variation in the CCL18 – CCL3 – CCL4 chemokine gene cluster influences HIV-1 transmission and AIDS disease progression. Am J Hum Genet 79: 120-128, 2006. [ PDF ]

Javanbakht, H., An, P., Gold, B., Petersen, D., O'hUigin, C., Nelson, G.W., O'Brien, S.J., Kirk, G., Detels, R., Buchbinder, S., Donfield, S., Shulenin, S., Song, B., Perron, M.J., Stemlau, M., Sodroski, J., Dean, M., and Winkler, C.A. Effects of human TRIM a polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. Virology 354: 15-27, 2006.

An, P., Duggal, P., Wang, L., O'Brien, S.J., Donfield, S., Goedert, J.J., Phair, J., Buchbinder, S., Kirk, G.D., and Winkler, C.A. HIV-1-associated CD4+ T-cell loss modulated by genetic variants of CUL5, encoding a host factor in the Apobec3-HIV-1 Vif pathway. Plos Genetics , 3: e19, 2007.

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