1. 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

2. 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

3. 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

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

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

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

7. 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

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

9. 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:

10. 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

11. Laboratory for Clinical Biochemistry Research
Larner College of Medicine

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

13. 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?