Immunogenetics Group
Soumitra Ghosh, MD, PhD
Since type 1 diabetes (T1D) is T-cell mediated and T-cell dependent disorder, changes in at-risk subjects leading to the disease have to occur at the T-cell level. Therefore, our Immunogenetics group, within the Max McGee National Research Center for Juvenile Diabetes, tries to characterize those changes for better predictive purposes and to gain an insight into pathogenesis. We are focused on the role genes play in T-cell phenotypes, an understanding of which will be important in preventing T1D. How do these genes affect T cells that then lead to T1D? Cellular phenotypes include production of cytokines (mainly IL-2), T-cell proliferation, regulatory T-cell (Treg) suppression, apoptosis and the expression of FoxP3. We are interested in both susceptibility and pathways genes that contribute in a major way to the genesis of an important T-cell phenotype. Many of the genes we study initially show allelic association to T1D in our Wisconsin and Finland genetic samples (see elsewhere for description of these projects). Understanding these genetic pathways will open up new ways to prevent this chronic disease. One of our strengths is our close working relationship with the Director of Diabetes at the Children's Hospital of Wisconsin, Dr. Ramin Alemzadeh. With expert help from our research Co-ordinators, Marilyn Koppen and Joanna Kramer, we obtain samples from T1D family subjects who visit the Diabetes Clinic regularly. We also ascertain samples from the Blood Research Institute of Southwestern Wisconsin (BRI) and from healthy control subjects. We have also been collaborating with Dr. William Hagopian in Seattle and Dr. Tom Ellis at the BRI, who help us define T1D risk status by a combination of autoantibody measurement and HLA genotyping. Finally, we are also involved in murine projects with our collaborators, Dr. Calvin Williams and Demin Wang to determine the in vivo role of genes and cells in protection from and pathogenesis of T1D.
With our multi-disciplinary approach that includes collaborations with other McGee faculty members, Dr. Marty Hessner and Dr. Xujing Wang, we have been able to chalk out a newer pathogenic mechanism for T1D that is being formally tested. Our future goals are to establish robust ways for preventing T1D linked with further collaborations with stem-cell groups to develop strategies for the ultimate cure of the disease by tissue engraftment and secondary prevention.
Journal Publication/Original Papers:
Glisic-Milosavljevic S, Waukau J, Jailwala P, Jana S, Khoo HJ, Albertz H, Woodliff J, Koppen M, Alemzadeh R, Hagopian W, Ghosh S. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction. PLoS ONE 2:e146, 2007.
Ghosh S, Schork N. Commentary on "Genetics of Type 2 Diabetes: The study of quantitative traits". Commentaries on Perspectives in Diabetes, pp213-214, 2006.
Nolan K, Schiller J, Ghosh S, Magnuson V Identification of a novel HLA-DQB1 allele, DQB1*060403, by sequence-based typing. Tissue Antigens, 68(5):456-457, 2006.
Geoffrey R, Jia S, Kwitek AE, Woodliff J, Ghosh S, Lernmark A, Wang X, Hessner MJ. Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. J Immunol 177(10):7275-7286, 2006.
Nittala A, Ghosh S, Stefanovski D, Bergman R, Wang X. Dimensional analysis of MINMOD leads to definition of the disposition index of glucose regulation and improved simulation algorithm. Biomed Eng Online, 5:44, 2006.
Wang X, Jia S, Meyer L, Xiang B, Chen LY, Jiang N, Moreno C, Jacob HJ, Ghosh S, Hessner MJ. Comprehensive quality control utilizing the prehybridization third-dye image leads to accurate gene expression measurements by cDNA microarrays. BMC Bioinformatics, 7(1): 378, 2006.
Wang X, He Z, Ghosh S. Investigation of the age-at-onset heterogeneity in type 1 diabetes through mathematical modeling. Mathematical Biosciences, 203(1):79-99, 2006.
Guo SW, Magnuson VL, Schiller JJ, Wang X, Wu Y, Ghosh S. Meta-Analysis of Vitamin D Receptor Polymorphisms and Type 1 Diabetes: A HuGE Review of Genetic Association Studies. Am J Epidemiology, 164(8):711-724, 2006.
Wu Y, Kajdacsy-Balla A, Strawn E, Basir Z, Halverson G, Jailwala P, Wang Y, Wang X, Ghosh S, Guo SW. Transcriptional Characterizations of differences between Eutopic and Ectopic Endometrium. Endocrinology, Jan;147(1): 232-246, 2006.
Glisic-Milosavljevic S, Waukau J, Jana S, Jailwala P, Rovensky J, Ghosh S. Comparison of apoptosis and mortality measurements in peripheral blood mononuclear cells (PMBCs) using multiple methods. Cell Prolif, 38: 301-311, 2005.
Hessner MJ, Wang X, Meyer L, Geoffrey R, Jia S, Fuller J, Lernmark A, Ghosh, S. Involvement of Eotaxin, Eosinophils, and Pancreatic Predisposition in Development of Type 1 Diabetes Mellitus in the BioBreeding Rat. J Immunol, 173:6993-7002, 2004.
Browning MB, Woodliff JE, Konkol MC, Pati NT, Ghosh S, Truitt RL, Johnson BD. CD150 identifies alloantigen CD4+25+ regulatory T cells. Cellular Immunology 227(2): 129-39, 2004.
Silander K, Scott LJ, Valle TT, Mohlke KL, Stringham HM, Wiles KR, Duren WL, Doheny KF, Pugh EW, Chines P, Narisu N, White PP, Fingerlin TE, Jackson AU, Li C, Ghosh S, Magnuson VL, et al. A Large Set of Finnish Affected Sibling Pair Families with Type 2 Diabetes suggests Susceptibility Loci on Chromosomes 6,11, and 14. Diabetes 53:821-829, 2004.
Pati N, Schowinsky V, Kokanovic O, Magnuson V, Ghosh S. A Comparison between SNaPshot, Pyrosequencing, and Biplex Invader SNP Genotyping Methods: Accuracy, Cost, and Throughput. JBBM 60:1-12, 2004.
Wang X, Jiang N, Feng X, Xie Y, Tonellato P, Ghosh S, Hessner MJ. A novel approach for microarray image processing using third-dye array visualization technology. IEEE trans Nanobioscience 4(2):193, 2003.
Waukau J, Jailwala P, Wang Y, Khoo HJ, Ghosh S, Wang X, Hessner M. The design of a gene chip for functional immunological studies on a high-quality control platform. Annals of NY Academyof Science. Annals of NY Academyof Science 1005:284, 2003.
Pati N, Ghosh S, Hessner MJ, Khoo HJ, Wang X. Difference in gene expression profiles between human CD4+CD25+ and CD4+CD25- T cells. Annals of NY Academyof Science 1005:279, 2003.
Hessner MJ, Wang, X, Khan S, Meyer L, Schlicht M, Tackes J, Datta MW, Jacob HJ, Ghosh S. Use of a three-color cNDA microarray platform to measure and control support-bound probe for improved data quality and reproducibility. Nucleic Acid Research 31(11): e60, 2003 Jun 1.
Wang X, Hessner M, Wu Y, Pati N, Ghosh S. Quantitative quality control in microarray experiments and the application in data filtering, normalization and false positive rate prediction. Bioinformatics 19(11): 1341-1347 2003 July 22.
Hessner M, Wang X, Hulse K, Meyer L, Wu Y, Nye S, Guo SW, Ghosh S. Three color cDNA microarrays: quantitative assessment through the use of fluorescein-labeled probes. Nucleic Acid Research 31(4):1-6, 2003.
Wang Y, Wang X, Guo SW, Ghosh S. Is hybridization truly competitive in two-color cDNA microarray experients? A theoretical modeling and its implications. Biotechniques 32(6):1342-1346, 2002.
Ghosh S, Tuomilehto J, Guo SW. Heterogeneity of type 1 diabetes. International Diabetes Monitor 141(3):18-20, 2002.
Wang X, Ghosh, S, Guo, SW Quantitative quality control in microarray image processing and data acquisition. Nucleic Acid Research Methods 29:15, 2001.
Mohlke KL, Lange EM, Valle T, Ghosh S, Magnuson VL, Silander K, et al. Linkage disequilibrium between microsatellite markers extends beyond 1 cM on chromosome 20 in Finns. Genomic Research 11:1221-1226, 2000.
Watanabe RM, Ghosh S, Langefeld CD, Valle T, Hauser ER, Magnuson VL, et al. The Finland-US investigation of non-insulin dependent diabetes mellitus (FUSION) genetic study: II. An autosomal genome scan for quantitative trait loci. American Journal of Human Genetics 67(5):1186-1200, 2000.
Ghosh S, Watanabe RM, Valle T, Hauser ER, Magnuson VL, Langefeld CD, et al. The Finland-US investigation of non-insulin dependent diabetes mellitus (FUSION) genetic study: I. An autosomal genome scan for genes that predispose to type 2 diabetes. 2000. American Journal of Human Genetics 67(5): 1174-1185, 2000.
Karanjawala Z, Kaariainen H, Ghosh S, Tannenbaum J, Martin C, Ally D, et al. Complete maternal isodisomy for chromosome 8 in an individual with an early- onset ileal carcinoid tumor. American Journal of Medical Genetics 93(3):207-210, 2000.
Brody LC, Baker PJ, Chines PS, Musick A, Molloy AM, Swanson DA, Kirke PN, Ghosh S, Scott JM, Mills JL. Methionine synthase: high resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects. Molecular Genetics and Metabolism 67:324-333, 1999.
Birznieks G, Ghosh S, Watanabe RM, Mitchell BD. The effect of phenotypic variation on detection of linkage in the COGA data. Genetic Epidemiology 17 (Suppl 1):S61-S66, 1999.
Watanabe RM, Ghosh S, Birznieks G, Duren WL, Mitchell BD. Application of a ordered subset analysis approach to the genetics of alcoholism. Genetic Epidemiology 17 (Suppl 1):S385-S390, 1999.
Mitchell BD, Ghosh S, Watanabe R, Slifer SH, Hsueh W-C, Birznieks G. Identifying influential individuals in linkage analysis: application to a quantitative trait locus detected in the COGA data. Genetic Epidemiology 17 (Suppl 1):S259-S264, 1999.
Listwak, S, Barrientos, RM, Koike, G, Ghosh, S, Gomez, M, Misiewicz, B, Sternberg, EM. Identification of a novel inflammation-protective locus in the Fischer rat. Mammalian Genome 10:362-365, 1999.
Watanabe RM, Valle T, Hauser ER, Ghosh S, Eriksson J, Kohtamaki K, Ehnholm C, Tuomilehto J, Collins FS, Bergman RN, and Boehnke M. for the FUSION study investigators. Familiality of quantitative metabolic traits in Finnish families with non-insulin dependent diabetes mellitus. Human Heredity 49:159-168, 1999.
Ghosh S, Watanabe RM, Hauser ER, Valle T, Magnuson VL, Erdos MR, et al. Type 2 Diabetes: Evidence for Linkage on Chromosome 20 in 716 Finnish Affected Sib Pairs. Proceedings of the National Academy of Sciences 96:2198-2203, 1999.
Ghosh S, Langefeld CD, Ally DS, Watanabe R, Hauser ER, Magnuson VL, et al. Trp64Arg variant of the b3-adrenergic receptor is not associated with type 2 diabetes or obesity in a large Finnish sample. Diabetologia 42:238-244, 1999.
Ghosh S, Hauser ER, Magnuson VL, Valle T, Ally DS, Karanjawala ZK, et al. A large sample of Finnish diabetics reveals no evidence for a NIDDM locus at 2qter. Journal of Clinical Investigation 102 (4): 704-709, 1998.
Valle T, Tuomilehto J, Bergman R, Ghosh S, Hauser ER, Eriksson J, et al. Mapping genes for non-insulin dependent diabetes mellitus: design of the Finland-United States Investigation of NIDDM genetics (FUSION) study. Diabetes Care 21(6):949-958, 1998.
Mitchell BD, Ghosh S, Schneider JL, Birznieks G, Blangero J. Power of variance component linkage analysis to detect epistasis. Genetic Epidemiology 14:1017-1022, 1997.
Perseghin G, Ghosh S, Gerow K, Schulman GI. Metabolic defects in lean, non-diabetic offspring of NIDDM patients: a cross-sectional study. Diabetes 46(6):1001-1010, 1997.
Ghosh S, Karanjawala ZE, Hauser ER, Ally D, Knapp JI, Rayman JB, et al. Methods for precise sizing, automated binning of alleles and reduction of error rates in large-scale genotyping using fluorescently-labeled dinucleotide markers. Genome Research 7(2):165-178, 1997.
Magnuson VL, Ally DS, Nylund SJ, Karanjawala ZE, Rayman JB, Knapp JI, Lowe AL, Ghosh S, Collins FC. Substrate nucleotide-determined non-templated addition of adenine by Taq DNA polymerase: Implications for PCR-based genotyping and cloning. BioTechniques 21:700-709, 1996.
Permutt MA, Ghosh S. Rat model contributes new loci for NIDDM susceptibility in man. Nature Genetics 12:4-6, 1996.
Ghosh S, Collins FC. The geneticist's approach to complex disease. Annual Review of Medicine 47:333-353, 1996.
Ghosh S, Schork NJ. Genetic analysis of type II diabetes: the analysis of quantitative traits. Diabetes 45:1-14, 1996.
Smith JR, Carpten JD, Brownstein MJ, Ghosh S, Magnuson VL, Gilbert DA, et al. Approach to genotyping errors caused by non-templated nucleotide addition by Taq DNA Polymerase. Genome Research 5:312-317, 1995.
Ghosh S. Probability and complex disease genes. Nature Genetics 9:223-224, 1995.
McDonald MT, Papenberg KA, Ghosh S, Glatfelter AA, Bisiecker BB, Helmbold EA, et al. A disease locus for Hereditary Haemorrhagic Telangiectasia maps to 9q33-. Nature Genetics 6:197-203, 1994.
Todd JA, Reed PW, Prins J-B, Bain SC, Palmer SM, Cordell HJ, Ghosh S, et al. Dissection of the pathophysiology of type 1 diabetes by genetic analysis. Journal of Autoimmunity 15 (Suppl):16-17, 1993.
Ghosh S, Palmer SM, Rodrigues N, Cordell HJ, Hearne CM, Cornall RJ, et al. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nature Genetics 4:404-409, 1993.
Risch N, Ghosh S, Todd JA. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application in NOD mouse and human IDDM, American Journal of Human Genetics. 53:702-714, 1993.
Prins JB, Todd JA, Rodrigues NR, Ghosh S, Hogarth PM, Wicker LS, et al. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice. Science 260: 695-698, 1993.
McAleer MA, Aitman TJ, Cornall RJ, Ghosh S, Hall JS, Hearne CM, et al. Linkage analysis of 84 microsatellite markers in intra- and interspecific backcrosses. Mammalian Genome 3:457-460, 1992.
Hearne CM, Ghosh S, Todd JA. Microsatellites for linkage analysis of genetic traits. TIGS 8:288-294, 1991.
Todd JA, Aitman TJ, Cornall, RJ, Ghosh S, Hall JS, Hearne CM, et al. Genetic analysis of complex multifactorial disease, autoimmune type 1 (insulin-dependent) diabetes. Res. Immun 142:483, 1991.
Hearne CM, McAleer MA, Love JM, Aitman TJ, Cornall RJ, Ghosh S, et al. Additional microsatellite markers for mouse genome mapping. Mammalian Genome 1: 273-282, 1991.
Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JS, Hearne CM, et al. Genetic analysis of autoimmune type I diabetes mellitus in mice. Nature 351:542-547, 1991.
Savill JS, Barrie R, Ghosh S, Muhlemann M, Dawson P, Pusey CD. Fatal Stevens-Johnson syndrome following urography with iopamidol in systemic lupus erythematosus. Postgraduate Medical Journal 64:392-394, 1988.
Book Chapters:
Hessner M, Wang X, Ghosh S. Genetics of type 1 diabetes. Diabetes Mellitus: A fundamental and clinical text. (eds. LeRoith D, Taylor S.I., Olefsky J.M.: Lippincott Williams & Wilkins Publishers), pp. 483-498, 2004.
Nye S, Ghosh S. Genetics of complex diseases. Genetics of Diabetes Mellitus, pp 1-25. Editor William L. Lowe, Jr, MD. Kluwer Academic Publishers. 2001.
Ghosh S. Positional cloning strategies to identify causal genes for type 2 diabetes mellitus. In Diabetes Mellitus: A fundamental and clinical text, (eds. LeRoith D. Taylor S.I., Olefsky J.: Lipincott-Raven Publishers). pp 664-674, 2000.
Ghosh S, Todd JA. Analysis of complex genetic diseases: lessons from type 1 diabetes. In Genome Analysis vol 3, Genes and Phenotypes (eds. Davies K.E. and Tilghman, S.M.: Cold SpringHarbor), pp. 79-104, 1991.