Max McGee National Research Center for Juvenile Diabetes

Jennifer Schiller, PhD

Type 1 diabetes mellitus (T1DM) is an autoimmune disease with a US Caucasian prevalence of approximately 15/100,000 and a much higher prevalence of around 40/100,000 in Finland. Also in contrast to the US where most T1DM cases are diagnosed before the age of 15, recent evidence suggests that most cases of T1DM in Finland are diagnosed after the age of 15. We aim to understand the molecular basis for both early- and late-onset T1DM in cohorts of US (Wisconsin) and Finnish subjects collected in collaboration with researchers in Finland (and supported by a grant from the Juvenile Diabetes Research Foundation). Our hope is that with this knowledge we could perhaps delay or even prevent the development of T1DM in younger, predisposed patients

There is ample evidence that certain gene sequences within the HLA region are strongly associated with T1DM disease development in the late-onset Finnish cohort. These sequence changes are distinct from those found in younger children with T1DM. We will therefore conduct a genome wide association (GWA) study and perform high-resolution genetic mapping of strongly associated regions to identify sequence variants which contribute the most to the development of diabetes, and play a role in delaying the age of disease onset as well. A comparison with a similar GWA study conducted in a younger-onset group in Cambridge, UK will help in this effort. After the initial analysis we will then focus on one chromosomal region that shows the maximum evidence for harboring a disease gene and conduct a region-specific analysis. This will comprise extensive typing of single nucleotide polymorphism (SNP) markers for case-control analyses (2000 cases + 2000 controls). We will also type singleton families, affected sib-pairs, affected parent-offspring families, dizygotic twins discordant for post-adolescent T1DM and sibships with both pre-adolescent and post-adolescent onset T1DM subjects. Sophisticated statistical analyses will follow including searches for gene-gene interactions. Our approach maximizes power in the final stages while allowing genotyping to proceed during the earlier stages of sample collection. A high resolution map on a very large Finnish sample along with sophisticated analysis should allow for the identification of candidate gene variants that can be examined functionally.

Publications:

1. Victoria L. Magnuson, Jennifer J. Schiller, Tao Wang and Soumitra Ghosh. 2007. Genetic association of HLA-DQB, PTPN22, INS and CTLA4 genes with younger and older age-of-onset type 1 diabetes. In preparation for submission.

2. Jennifer J. Schiller, Matthew Cusick and David D. Eckels. 2007. Human hepatitis C virus induces expansion of functional epitope-specific CD4+CD25+ regulatory T cells. In preparation for submission.

3. Shuping Wang, Rico Buchli, Jennifer J. Schiller, Jianen Gao, Jane H. Wang, William H. Hildebrand and David D. Eckels. 2007. Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity. In preparation for submission.

4. K. Nolan, J. Schiller, S. Ghosh and V. Magnuson. 2006. Identification of a novel HLA-DQB1 allele, DQB1*060403, by sequence-based typing. Tissue Antigens 68:456-457.

5. Sun-Wei Guo, Victoria Magnuson, Jennifer J. Schiller, Xujing Wang, Yan Wu and Soumitra Ghosh. 2006. Vitamin D receptor polymorphisms and type 1 diabetes: a meta-analysis of genetic association studies. Am J Epidemiol 164:711-724.

6. Stephen J. Zoog, Jennifer J. Schiller, Justin A. Wetter, Nor Chejanovsky and Paul D. Friesen. 2002. Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo. EMBO J 21(19):5130-5140.

7. Susan C. Baker, Amornrat Kanjanahaluethai, Nathan M. Sherer, David D. Axtell, and Jennifer J. Schiller. 2001. Exploiting DNA immunization to generate polyclonal antisera to coronavirus replicase proteins. In: Ehud Lavi et al. (Eds.), The Nidoviruses (Coronaviruses and Arteriviruses), Kluwer Academic/Plenum Publishers, pp. 283-289.

8. Stephanie T. Shi, Jennifer J. Schiller, Amornrat Kanjanahaluethai, Susan C. Baker, Jon-Wong Oh, and Michael M.C. Lai. 1999. Colocalization and membrane association of murine hepatitis virus gene 1 products and de novo synthesized viral RNA in infected cells. J Virol 73:5957-69.

9. Jennifer J. Schiller, Amornrat Kanjanahaluethai and Susan C. Baker. 1998. Processing of the coronavirus MHV-JHM polymerase polyprotein: Identification of precursors and proteolytic products spanning 400 kilodaltons of ORF1a. Virology 242:288-302.

10. Jennifer J. Schiller and Susan C. Baker. 1998. Maturation of the polymerase polyprotein of the coronavirus MHV strain JHM involves a cascade of proteolytic processing events. Adv Exp Med Biol 440:135-9.

11. Jennifer J. Schiller and Susan C. Baker. 1998. Coronavirus papain-like endopeptidases. In: Alan J. Barrett, Neil Rawlings and J. Frederick Woessner, Jr. (Eds.), Handbook of Proteolytic Enzymes, Academic Press, pp. 681-3.

12. Hong-Qiang Gao, Jennifer J. Schiller and Susan C. Baker. 1996. Identification of the polymerase polyprotein products p72 and p65 of the murine coronavirus MHV-JHM. Virus Res 45:101-9.