Is There A Role For “Deep Phenotyping” ? VACS-COMpAAAS Scientific Meeting December 11-13, 2016 Precision Medicine: Is There A Role For “Deep Phenotyping” ? Russell P. Tracy, PhD, ABCC, FAHA Departments of Pathology & Laboratory Medicine and Biochemistry Laboratory for Clinical Biochemistry Research Larner College of Medicine at the University of Vermont Laboratory for Clinical Biochemistry Research Larner College of Medicine

Precision Medicine Most medical treatments have been designed for the “average patient.” Treatments can be very successful for some patients but not for others. Precision Medicine takes into account individual differences in people’s genes, environments, and lifestyles. White House Precision Medicine Website Laboratory for Clinical Biochemistry Research Larner College of Medicine

Precision Medicine Chronic diseases are mentioned But majority of the research: cancer. Environment, behaviors, current physiology are mentioned But emphasis: genomics. Other “-omics” are coming along (microbiomics, metabolomics, methylomics, transcriptomics, proteomics) But application is only now emerging Biomarkers are mentioned But usually as something that needs to be developed Laboratory for Clinical Biochemistry Research Larner College of Medicine

Intermediate Phenotypes Biological Phenotypes Molecular Phenotypes Clinical Phenotypes Agnostic Patterns Detailed Pathways Laboratory for Clinical Biochemistry Research Larner College of Medicine

Example discussed today: Cellular Epidemiology “Deep Phenotyping” Example discussed today: Cellular Epidemiology

Inflammation and CVD Risk 2003 (2.07 mg/l) CRP = 1 mg/l CRP = 3 mg/l 2008 2009

sIL-2Ra (CD25) In CHS, associations with all cause mortality, cardiovascular mortality, and coronary heart disease In GWAS >50 SNPs in near IL2RA gene were associated (p<5x10-8) with sIL-2Rα levels in EAs, explaining >12% of the variation (none in AAs) Preliminary analyses suggests 4 major functional variants No individual SNPs were significantly associated with events; work continues on a gene score in larger populations

Inflammation and immune activation are risk factors for CVD in the general population and in HIV+ populations; why??

Both Innate and Adaptive Immunity are Involved: Plus other components of the Innate Immune System such as: - Complement - Pentraxins * CRP * SAP * PTX-3 MØ TF IIa CAMs, Selectins Oxidative Stress IL-6 CRP IFN-g + + Other Inflammation Laboratory for Clinical Biochemistry Research University of Vermont Modified from Hansson G N Engl J Med 2005;352:1685-95

MESA-Inflammation: a Cellular Epidemiological Study Laboratory for Clinical Biochemistry Research Larner College of Medicine Baseline in 2000 – 2002 n = 6814 men and women in 4 ethnicities Caucasian, African American, Hispanic, and Chinese; from 6 US communities 45 to 84 years old, free of clinically apparent CVD 1000 individuals randomly selected in exam 4, 2006 – 2007 Many atherosclerosis outcomes: CAC, IMT Cellular epidemiology including T Cell phenotypes Samples shipped overnight – many logistic hurdles

Laboratory for Clinical Biochemistry Research Larner College of Medicine

Evidence for a role for immune activation, immunosenescence or both…. Laboratory for Clinical Biochemistry Research University of Vermont

Conceptual model of how immune function interacts with atherosclerosis & aging Coagulation; also part of “inflammation” (e.g., M activation, IL-6, etc) “Stimulators” that don’t invoke adaptive immunity: Wound healing MT & endotoxemia Alcoholic liver damage Smoke-related lung damage etc Innate Immunity; “inflammation” (e.g., M activation, IL-6, etc) ? IFN-γ MMP deposition Immune stimulators: Viruses (e.g. CMV, HIV); Bacteria Autoimmune disorders RA, SLE Th1 When there is sufficient OXLDL: ATHEROSCLEROTIC PLAQUE & rupture Increasing immunosenescence Th2 Naive T cells Effector/Memory One of many aspects is T Helper function; other aspects could be discussed here, such as Treg, Th17, etc I would put the Olson and Amirati data first, and then this slide, before the Specific Aims. I’d finish w the specific aims and then the “therapeutics” slide Adaptive Immunity (e.g. CD4+ cells, CD8+ cells, B cells) Increasing utilization of adaptive immunity leads to : Immunosenescence Increased burden on innate immunity (inflammation) increased infectious burden due to inefficient immune response increased cancer risk due to loss of immune surveillance Increased Effector/Memory population Proinflammatory Increased SASP population (Senescence-Associated Secretory Phenotype; CD28-) Ho: this happens slowly in HIV- people but more rapidly in HIV+ people All chronic diseases?