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Incorporating Genomics in Epidemiological Research: Examples from the Partnerships for Genomics and Molecular Epidemiology Judith T. Lessler March 18, 2005 RTI International is a trade name of Research Triangle Institute 3040 Cornwallis Road Phone 919-541-6631 ■ P.O. Box 12194 ■ Research Triangle Park, North Carolina, USA 27709 e-mail [email protected] NIH Research “Solving the puzzle of complex diseases, from obesity to cancer, will require a holistic understanding of the interplay between factors such as genetics, diet, infectious agents, environment, behavior, and social structures.” Zerhouni SCIENCE VOL 302 October 3, 2003 NIH Directions Focus on interdisciplinary teams to solve large scientific problems Provide a seed mechanism for high-risk research Create programs to forge public-private partnerships NIH Institutes focus on Genomics and gene-environment interactions Sharing of data; public data resources NIMH and Mood Disorders Mood disorders (depression and bipolar disorder) are highly heritable Non-genetic factors, particularly stress are significant in triggering episodes of mood disorders Breaking Ground, Breaking Through: The Strategic Plan for Mood Disorders Research, National Institutes of Mental Health, July 2002 Influence of Life Stress on Depression (Caspi, et. al, 2003) Prospective-longitudinal cohort study of stress and depression Functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene Individuals with the short allele of the 5-HTT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in response to stress Caspi, A, et. al (2003) Influence of Life Stress on Depression, Science, Vol. 301, July 18, 2003 Partnerships for Genomics and Molecular Epidemiology (PGME) Goal: Build a research program that would allow us to conduct complex research that illuminates the interaction between genetics and the environment Took a building block approach Development of internal capabilities and experience Partnering with universities and other organizations that have complementary capabilities Partnerships for Genomics and Molecular Epidemiology (PGME) Bioinformatics Statistical Genetics Proteomics Public understanding of genetics/genomics Epidemiology Epidemiology: a Core Competency that Binds Disciplines Laboratory Molecular Sciences Health Sciences Epidemiology Biostatistics; Informatics Social and Behavioral Sciences PGME: Bioinformatics Data management and data integration Data types: clinical, biological assays, sequence data, gene expression, and protein expression Integration of external data sets on genes, proteins, biological pathways High performance computing 64-cpu Linux Cluster PGME: Bioinformatics http://gdbwww.gdb.org/ Statistical Genetics Data mining Mathematical modeling Statistical Genetics: genetic linkage analysis, genetic association mapping, gene-environment interactions Analysis of microarray and proteomic data Statistical and data coordinating centers Proteomics Methodologies: Tissue Protein Isolations 2-D Gel Separations Quantitative Image Analysis Immunological analyses Technologies: Instrument development Alternative separations Protein characterization Quantitative analysis Proteomics Equipment: TOF-TOF 2 Ion Traps (Linear and 3-D) 2-D gel electrophoresis platform Technology Development: Shot-gun proteomics RTI Shotgun Proteomics IPG Strip Peptide Work Flow •• •• • K K R R K Enzymatic Digest of Protein MIxture Load and Focus Peptides on IEF Strip Database Searching and pI Based Data Filtering Cut IEF Strip Into Fractions Extract Peptides from IEF Fractions Data-Dependent LC-MS/MS Analysis Partnerships Expertise in sequencing and gene expression Clinical expertise: immunology, vaccine response, drug and alcohol abuse, heart disease, pre-term labor, microbial systems, pulmonology, etc., high performance computing, software development Duke, UNC, NC State, East Carolina, IBM, SAS, Alpha-Gamma Inc, Virginia Commonwealth University, and from India: Institute of Statistical Sciences, National Institute of Cholera and Enteric Diseases [NICED] and Institute of Molecular Medicine NIAID Program on Immunity to Vaccines/Infections The objective is to understand role of polymorphisms in genes of innate and adaptive immunity in modulating the response to vaccines for two gastrointestinal tract infections: typhoid and cholera. RTI International Institute of Molecular Medicine National Institute of Cholera and Enteric Diseases Duke University Immunity to Vaccines/Infections Collect blood and saliva from 1000 participants for each vaccine in Kolkata, India, at days 0, 3, and 28 Perform vaccine related immunological assays on all biospecimens and classify subjects as non-, poor-, and good responders using ELISA and vibrocidal antibody assays Discover and validate SNP polymorphisms and screen all participants’ DNA for SNPs to 14 innate immunity genes and genome scans for adaptive immunity genes; Immunity to Vaccines/Infections Protein/peptide expression of 11 protein mediators of innate/adaptive immunity and 22 proteins involved in cell stimulation and signal transduction. Using LC/MS, immunoassay, and flow cytometry Also using 2-D gel MS/MS on 100-200 proteins, protein isoforms and protein fragments to determine more generalized effects of immune activation, signal transduction and general response to vaccination, Analysis if association between vaccine response and SNPs, haplotypes, or protein expression Immunity to Vaccines/Infections Data will be included in a NIAID sponsored data system that will integrate data from 5 other similar trials Bioinformatics Integration Support System (BISS) Opportunities Abound NC has many resources that can be used to develop partnerships Appreciate work that Donna Spoon and others have done to create opportunities for sharing information and developing partnerships PGME Team (partial) Diane Wagener, PhD, Director of Genetic Epidemiology and project director for the vaccine research project Jim Stephenson, PhD, Director of Proteomics Group Jamie Cuticchia, PhD, Director of Bioinformatics Georgiy Bobashev, PhD, Director of Statistical Genetics Partnerships for Genomics and Molecular Epidemiology Partnership contacts: Judy Lessler: [email protected] -- 919-541-6631 Joe Pratt: [email protected] – 919-541-6463