BIOMEDICAL SCIENCES GRADUATE PROGRAM SUMMER 2016

Transcription

1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM SUMMER 2016 Katherine Hartmann PhD Candidate Addressing the Missing Heritability of Coronary Artery Disease Friday 29 th July 2016 L045 James 10:00 am

2 VITA 21 October Born Cincinnati, Ohio May B.A. Biology, Cornell University 2010-present MSTP Trainee, Ohio State University COMMITTEE MEMBERS Wolfgang Sadee Ray Hershberger Rebecca Jackson Joseph Kitzmiller

3 ABSTRACT There is often a strong genetic component to human health and disease reflected in the importance of an individual s family history in clinical practice. This is certainly true for coronary artery disease (CAD), with heritability estimates calculated by comparing concordance between monozygotic and dizygotic twins range from 40 to 60%. Sequencing of the human genome in the early 2000s led to the advent of Genome Wide Association Studies (GWAS) that test millions of variants across the genome for an association with disease. These large-scale studies have identified 58 loci associated with risk of CAD; yet each variant contributes relatively little to disease risk (odds ratios range from 1.01 to 1.92) and in total they account for only about 10% of genetic risk. The remainder of the genetic risk remains unexplained, a phenomenon termed missing heritability. This work aims to address this missing heritability by considering the potential for non-linear interactions contributing to CAD risk. The following chapters aim to uncover disease relevant interactions. The first is a survey of genes implicated in CAD by GWAS. It uses expression as a guide to prioritize the relevant gene locus for each GWAS variant, revealing loci with multiple protein-coding and non-coding transcripts and expression patterns that cannot be accounted for by a single functional variant. The next chapter considers differential expression of GWAS-based candidate genes in the context of disease. Gene expression, which incorporates both genetic and environmental factors, is used as a guide to search for interactions. We identify non-linear interactions between gene expression patterns that are associated with risk of myocardial infarction. The next two chapters both focus on specific gene loci, allowing greater resolution to probe molecular mechanisms in detail. The first of these considers the nicotinic receptor locus, which consists of three genes: CHRNA5, CHRNA3, and CHRNB4 that each form subunits of the nicotinic receptor. We identify three main signals (rs , rs88053, and rs1948) associated with gene expression, which form diplotypes that better account for risk nicotine dependence than individual variants, thus demonstrating the importance of

4 interactions. The final chapter reveals a potential role for Cholesteryl Ester Transfer Protein (CETP), a drug target for CAD, in immune-related functions based on expression and coexpression patterns. It considers three candidate variants, two having opposing effects on expression (rs and rs ) and one associated with splicing (rs5883). Each of these studies supports the role for non-linear, non-additive interactions contributing to coronary artery disease.

5 RECENT ABSTRACTS AND PRESENTATION September 2014 Co-expression of Cholesterol Metabolism Genes Reveals Complex Feedback System, Pharmacogenomics Research Network (Rochester, MN) [Presentation] January 2015 Accessing Large Datasets, NCH/OSU Genetics and Genomics Symposium: Big Data and Big Ideas in Genomic Medicine (Columbus, OH) [Presentation] Hartmann K. W. Sadee. Testing genetic factors modulating splicing of cholesteryl ester transfer protein (CETP) mrna a potential cardiovascular biomarker. National MD/PhD Student Conference, Keystone, Colorado, July 2011 [Poster] Hartmann K., M. Seweryn, R. Smith, G. Rempala, and W. Sadee. Exploring the Role of Non-coding RNAs in Determining Tissue Specificity. Genotype Tissue Expression Project (GTEx) Community Meeting, Boston, Massachusetts, June 2014 [Poster] Hartmann K. amd M. Seweryn. Variability of Protein Coding and Non-Coding Co-expression Patterns. Research in Computational and Molecular Biology, Warsaw, Poland, April 2015 [Poster] Hartmann K., M. Seweryn, and W. Sadee. Role of Genetic Variants in Cholesteryl Ester Transfer Protein. American Society for Human Genetics, Baltimore, Maryland, October 2015 [Poster]

6 RECENT PUBLICATIONS J. P. Kitzmiller, P. F. Binkley, S. R. Pandey, A. M. Suhy, D. Baldassarre, and K. Hartmann, Statin pharmacogenomics: pursuing biomarkers for predicting clinical outcomes., Discov. Med., vol. 16, no. 86, pp , Aug A. Suhy, K. Hartmann, L. Newman, A. Papp, T. Toneff, V. Hook, and W. Sadee, Genetic variants affecting alternative splicing of human cholesteryl ester transfer protein., Biochem. Biophys. Res. Commun., vol. 443, no. 4, pp , Jan W. Sadee, K. Hartmann, M. Seweryn, M. Pietrzak, S. K. Handelman, and G. A. Rempala, Missing heritability of common diseases and treatments outside the protein-coding exome., Hum. Genet., vol. 133, no. 10, pp , Oct R. Lu, R. M. Smith, M. Seweryn, D. Wang, K. Hartmann, A. Webb, W. Sadee, and G. A. Rempala, Analyzing allele specific RNA expression using mixture models., BMC Genomics, vol. 16, no. 1, p. 566, Jan S. K. Handelman, M. Seweryn, R. M. Smith, K. Hartmann, D. Wang, M. Pietrzak, A. D. Johnson, A. Kloczkowski, and W. Sadee, Conditional entropy in variation-adjusted windows detects selection signatures associated with expression quantitative trait loci (eqtls)., BMC Genomics, vol. 16 Suppl 8, p. S8, Jan A. Suhy, K. Hartmann, A. C. Papp, D. Wang, and W. Sadee, Regulation of cholesteryl ester transfer protein expression by upstream polymorphisms: reduced expression associated with rs , Pharmacogenet. Genomics, Jun F. Makadia, P. P. Mehta, C. E. Wisely, J. E. Santiago-Torres, K. Hartmann, M. J. Welker, and D. Habash, Creating and Completing Service-Learning within Medical School Curricula: From the Learner s Perspective, International Journal of Medical Students, vol. 3, no Aug-2015.

7 P. P. Mehta, J. E. Santiago-Torres, C. E. Wisely, K. Hartmann, F. A. Makadia, M. J. Welker, and D. L. Habash, Primary Care Continuity Improves Diabetic Health Outcomes: From Free Clinics to Federally Qualified Health Centers., J. Am. Board Fam. Med., vol. 29, no. 3, pp , May-June AWARDS AND HONORS MD/PhD Leadership and Academic Achievement Scholarship MD/PhD Leadership and Academic Achievement Scholarship University Fellowship 2015 Research in Computational and Molecular Biology Travel Fellowship TL1 Training Award FUTURE PLANS I am moving to Brussels in September for a Fulbright fellowship at the European Organisation for the Research and Treatment of Cancer (EORTC). While there, I will be studying cancer evolution. During my PhD, I became quite impressed with the well-preserved linkage between genetic variants and interested in the evolutionary pressures that drive these patterns. I think evolution is the key to unlocking our understanding of genetics and hope to gain more expertise in this area. I will be returning to Ohio State after the fellowship to complete my last two years of medical school.