Cheryl Ann Winkler, Ph.D.
Cheryl Ann Winkler, Ph.D.
Senior Investigator (Contr)
Head, Molecular Genetic Epidemiology Studies Section

Center for Cancer Research
National Cancer Institute

Building 560, Room 11-64
Frederick, MD 21702-1201
301-846-5747

Dr. Winkler discovered the association between a chromosome 22 region containing MYH9 and APOL1 with kidney disease. APOL1 variants are predictors of chronic kidney disease and a marker for progression (odds ratio 2-89), but they also protect against trypanosomiasis. We are now identifying the spectrum of phenotypes associated with APOL1 risk alleles in USA and African cohorts and investigating the pathophysiological mechanism leading to glomerular injury. We are studying the influence of APOL1 risk variants on living kidney donors and on kidney graft survival in African Americans. A goal of this research is to develop precision biomarkers for diagnostics and prognostics and to identify druggable targets to treat kidney disease.

Areas of Expertise
genetic epidemiology, APOL1, health disparities, kidney disease, admixture mapping, global health

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 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. HIV-associated nephropathy (HIVAN) occurs in 10% of untreated HIV persons of African descent but is rarely observed in non-Africans. Together with Dr. Jeffrey Kopp, NIDDK, we have accrued over 1200 FSGS and HIVAN 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. Dr. Winkler led the team that identified MYH9 as a major susceptibility gene for common etiologies of chronic and end stage kidney disease in 2008.
     
  2. 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.
       
  3. 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.
     
  4. Identify genetic factors that 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.
Scientific Focus Areas:
Computational Biology, Genetics and Genomics, Health Disparities, Virology
Selected Recent Publications
  1. Thomson R, Genovese G, Canon C, Kovacsics D, Higgins MK, Carrington M, Winkler CA, Kopp J, Rotimi C, Adeyemo A, Doumatey A, Ayodo G, Alper SL, Pollak MR, Friedman DJ, Raper J.
    Proc. Natl. Acad. Sci. U.S.A. 111: E2130-9, 2014. [ Journal Article ]
  2. Liang Y, Tang W, Huang T, Gao Y, Tan A, Yang X, Zhang H, Hu Y, Qin X, Li S, Zhang S, Mo L, Liang Z, Shi D, Huang Z, Guan Y, Zhou J, Winkler C, O'Brien SJ, Xu J, Mo Z, Peng T.
    PLoS ONE. 9: e97923, 2014. [ Journal Article ]
  3. Galanter JM, Gignoux CR, Torgerson DG, Roth LA, Eng C, Oh SS, Nguyen EA, Drake KA, Huntsman S, Hu D, Sen S, Davis A, Farber HJ, Avila PC, Brigino-Buenaventura E, Lenoir MA, Meade K, Serebrisky D, Borrell LN, Rodríguez-Cintrón W, Estrada AM, Mendoza KS, Winkler CA, Klitz W, Romieu I, London SJ, Gilliland F, Martinez F, Bustamante C, Williams LK, Kumar R, Rodríguez-Santana JR, Burchard EG.
    J. Allergy Clin. Immunol. 134: 295-305, 2014. [ Journal Article ]
  4. An P, Goedert JJ, Donfield S, Buchbinder S, Kirk GD, Detels R, Winkler CA.
    J. Infect. Dis. 210: 1539-48, 2014. [ Journal Article ]
  5. Thameem F, Igo RP, Freedman BI, Langefeld C, Hanson RL, Schelling JR, Elston RC, Duggirala R, Nicholas SB, Goddard KA, Divers J, Guo X, Ipp E, Kimmel PL, Meoni LA, Shah VO, Smith MW, Winkler CA, Zager PG, Knowler WC, Nelson RG, Pahl MV, Parekh RS, Kao WH, Rasooly RS, Adler SG, Abboud HE, Iyengar SK, Sedor JR.
    PLoS ONE. 8: e81888, 2013. [ Journal Article ]

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 Senior Investigator in the Basic Research Laboratory and is a Principal Investigator or Co-Investigator for several multicenter or international studies: The Hemophilia Growth and Development Study, the Hemophilia Genetics Inhibitor Study, the Family Investigation of Nephropathy and Diabetes, and the Host Genetics Study of HIV Disease in Botswana.

Name Position
Ping An MD, MPH Staff Scientist (Contr)
Elizabeth A. Binns-Roemer Research Assistant (Contr)
Victor A. David Research Geneticist
Sarwat Kazmi Summer Student
Sophie M. Limou Ph.D. Postdoctoral Fellow (Contr)
Efe Sezgin Ph.D. Guest Researcher (Contr)
Noah Totsline Summer Student

Summary

Dr. Winkler discovered the association between a chromosome 22 region containing MYH9 and APOL1 with kidney disease. APOL1 variants are predictors of chronic kidney disease and a marker for progression (odds ratio 2-89), but they also protect against trypanosomiasis. We are now identifying the spectrum of phenotypes associated with APOL1 risk alleles in USA and African cohorts and investigating the pathophysiological mechanism leading to glomerular injury. We are studying the influence of APOL1 risk variants on living kidney donors and on kidney graft survival in African Americans. A goal of this research is to develop precision biomarkers for diagnostics and prognostics and to identify druggable targets to treat kidney disease.

Areas of Expertise
genetic epidemiology, APOL1, health disparities, kidney disease, admixture mapping, global health

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 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. HIV-associated nephropathy (HIVAN) occurs in 10% of untreated HIV persons of African descent but is rarely observed in non-Africans. Together with Dr. Jeffrey Kopp, NIDDK, we have accrued over 1200 FSGS and HIVAN 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. Dr. Winkler led the team that identified MYH9 as a major susceptibility gene for common etiologies of chronic and end stage kidney disease in 2008.
     
  2. 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.
       
  3. 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.
     
  4. Identify genetic factors that 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.
Scientific Focus Areas:
Computational Biology, Genetics and Genomics, Health Disparities, Virology

Publications

Selected Recent Publications
  1. Thomson R, Genovese G, Canon C, Kovacsics D, Higgins MK, Carrington M, Winkler CA, Kopp J, Rotimi C, Adeyemo A, Doumatey A, Ayodo G, Alper SL, Pollak MR, Friedman DJ, Raper J.
    Proc. Natl. Acad. Sci. U.S.A. 111: E2130-9, 2014. [ Journal Article ]
  2. Liang Y, Tang W, Huang T, Gao Y, Tan A, Yang X, Zhang H, Hu Y, Qin X, Li S, Zhang S, Mo L, Liang Z, Shi D, Huang Z, Guan Y, Zhou J, Winkler C, O'Brien SJ, Xu J, Mo Z, Peng T.
    PLoS ONE. 9: e97923, 2014. [ Journal Article ]
  3. Galanter JM, Gignoux CR, Torgerson DG, Roth LA, Eng C, Oh SS, Nguyen EA, Drake KA, Huntsman S, Hu D, Sen S, Davis A, Farber HJ, Avila PC, Brigino-Buenaventura E, Lenoir MA, Meade K, Serebrisky D, Borrell LN, Rodríguez-Cintrón W, Estrada AM, Mendoza KS, Winkler CA, Klitz W, Romieu I, London SJ, Gilliland F, Martinez F, Bustamante C, Williams LK, Kumar R, Rodríguez-Santana JR, Burchard EG.
    J. Allergy Clin. Immunol. 134: 295-305, 2014. [ Journal Article ]
  4. An P, Goedert JJ, Donfield S, Buchbinder S, Kirk GD, Detels R, Winkler CA.
    J. Infect. Dis. 210: 1539-48, 2014. [ Journal Article ]
  5. Thameem F, Igo RP, Freedman BI, Langefeld C, Hanson RL, Schelling JR, Elston RC, Duggirala R, Nicholas SB, Goddard KA, Divers J, Guo X, Ipp E, Kimmel PL, Meoni LA, Shah VO, Smith MW, Winkler CA, Zager PG, Knowler WC, Nelson RG, Pahl MV, Parekh RS, Kao WH, Rasooly RS, Adler SG, Abboud HE, Iyengar SK, Sedor JR.
    PLoS ONE. 8: e81888, 2013. [ Journal Article ]

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 Senior Investigator in the Basic Research Laboratory and is a Principal Investigator or Co-Investigator for several multicenter or international studies: The Hemophilia Growth and Development Study, the Hemophilia Genetics Inhibitor Study, the Family Investigation of Nephropathy and Diabetes, and the Host Genetics Study of HIV Disease in Botswana.

Team

Name Position
Ping An MD, MPH Staff Scientist (Contr)
Elizabeth A. Binns-Roemer Research Assistant (Contr)
Victor A. David Research Geneticist
Sarwat Kazmi Summer Student
Sophie M. Limou Ph.D. Postdoctoral Fellow (Contr)
Efe Sezgin Ph.D. Guest Researcher (Contr)
Noah Totsline Summer Student