DNA Studies (Genetic Studies) Disclosure Statement. Definition of Genomics. Outline. Immediate Present and Near Future

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1 Advances in Genetic Marker Evaluation Prior to Vascular Access Creation Timmy Lee, M.D., M.S.P.H., F.A.C.P., F.A.S.N. Assistant Professor of Medicine Division of Nephrology and Hypertension University of Cincinnati Academic Health Center February 25, 2012 Immediate Present and Near Future Clinical and financial need for new discoveries in vascular access Growing patient population Few effective therapies Still poor understanding of mechanisms of vascular access dysfunction We live in exciting times for vascular access research Advancement in technology (imaging, devices, and genomic technology) Genomic technology presents a great an opportunity to advance the science and clinical care forward Disclosure Statement Consultant: Proteon Therapuetics Shire Funding: National Institutes of Health (5K23DK ) National Kidney Foundation Franklin McDonald/Fresenius Young Investigator Award Definition of Genomics Genomics is the study of all the genes of a cell or tissue, at the DNA (genotype), mrna (gene expression), or protein levels Genomic Biomarkers: measurable DNA and/or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other interventions. Food and Drug Administration Definition Outline Principles of Genomics Tools of Genomic Technology (DNA and RNA) Role of Genomics in Future Research and Clinical Care in Vascular Access Dysfunction DNA Studies (Genetic Studies) 1

2 Genetic Biomarkers Genetic studies (DNA studies) Single nucleotide polymorphisms (SNPs) Variability of short sequence repeats Haplotypes DNA modifications, e.g., methylation Deletions or insertions of (a) single nucleotide(s) Copy number variations Cytogenetic rearrangements, e.g., translocations, duplications Other Genetic Polymorphisms Studies in Vascular Access Polymorphisms of Factor V Leiden Polymorphisms of Tumor Necrosis Factor alpha (TNF-α) Endothelial nitric oxide synthase gene intron 4 (VNTR) polymorphism DNA Variation >99.9 % of DNA sequence is identical between any two chromosomes. Still many variations in DNA sequences Some DNA variations are responsible for biological changes Genetic polymorphism: The existence together of many forms of DNA sequences at a locus within the population. Genetic Association Studies Short-term Goal: Identify genetic variants that explain differences in phenotype among individuals in a study population If association found, then further study can follow to Understand mechanism of action and disease etiology in individuals Characterize relevance and/or impact in more general population Long-term goal: to inform process of identifying and delivering better prevention and treatment strategies Adapted from Lecture by TE Fingerlin Adapted from Lecture by TE Fingerlin Genetic Polymorphism Studies in Dialysis Access HO-1 ACE MTHFR TGF-β1 Gene Genotype Primary Outcome Studied S/S L/S L/L D/D I/D I/I C/C T/C T/T High, Intermediate,and Low Producers Primary Unassisted Patency (N=603) 12 month AVF patency (N=137) AVF thrombosis (N=337) Cumulative Survival (N=120) Results L/Lgenotype worse primary unassisted patency No difference in patencyby genotype T/Tgenotype associated with more AVF thrombosis Higher producer haplotypehad worse cumuative surival Reference Lin et al, KI, 2006 Heine et al, AJN, 2004 Fukasawa, AJKD, 2003 Heine, KI, 2003 RNA Studies (Gene Expression) 2

3 RNA Biomarkers RNA studies RNA levels (gene expression) RNA sequences RNA processing, e.g., splicing and editing microrna levels Heat Map Profile of Genes Expression in Atherosclerotic PAD Normal vs Intermediate Normal vs Advanced Genes of Interest Fu et al, BMC Genomics, Overview of Microarray Analysis Pathway Analysis from Microarray Data Fu et al, BMC Genomics, Quackenbush J. N Engl J Med 2006 Histology of Atherosclerotic Lesions in Peripheral Artery Disease Gene Expression Signatures Associated with Prognosis in Liver Cancer Normal Intermediate Fu et al, BMC Genomics, Advanced Hoshida et al,. N Engl J Med. 3

4 Use of a Gene-Expression Profile to Define the Risk of Relapse in Patients with Early-Stage Breast Cancer Genomic-Based Prediction Risk Models from Vascular Access Clinical Studies Patient Tissue and Blood Genotyping Expression Profiling Proteomic Profiling Epigenetics Clinical Data Biological Database Demographic Data McDermott U et al. N Engl J Med Adapted in part from Miller et al, JACC 2007 Future Role of Genomics in Vascular Access Research and Clinical Care Investigative Pathways Leading from Gene Discovery to Clinical Application in Vascular Access Genomic Discovery DNA and RNA Studies Hypothesis Driven Research Molecular and Cellular Studies Animal Models Disease Risk- Prediction Risk Factor Assessment Disease Pathophysiology Clinical Trials Biomarkers Studies Personalized Therapy Patient Assessment Clinical Intervention Adapted in part from O'Donnell CJ, Nabel EG. N Engl J Med Randomized Controlled Trials in Internal Medicine Subspecialties Personalized Therapy for Vascular Access Patients using Genomics Assess Risk Targeted Therapies Refine Assessment Local Therapies Local Therapies Endovascular Monitor Progression Maintenance Therapies Chronic Kidney Disease and ESRD (prior to access creation) Surgical Vascular Creation Intervention Follow up of Progression Baseline risk Clinical Data SNPs Surgical risk Gene Expression Disease Progression SNPs Gene Expression Therapeutic Decision Support Response Genomics Pharmocogenomics Sources of New Biomarkers Strippoli G F M et al. JASN 2004 Adapted in part from Ouzounian et al Can J Cardiol,

5 Take Home Messages Very few genomics studies in vascular access Genomics will play in important role in understanding pathophysiology, predicting clinical vascular access risk failure, and design of future clinical trials Genomics will play an important role of personalized care of patient s vascular access in future 5