1. Genetic Testing for the Clinician
James Strait M.D., Ph.D.
Head, Human Cardiovascular Studies
Lab of Cardiovascular Sciences
National Institute on Aging
National Institutes of Health

2. I have no real or apparent conflicts of interest to report.
James Strait, MD, PhD
I have no real or apparent conflicts of interest to report.

3. National Institute on Aging National Institutes of Health
Baltimore Longitudinal Study of Aging
SardiNIA Study

4. DNA

5. The modern era of Genetic Medicine Rare vs. Common Diseases
Cystic Fibrosis
Hypertension
CFTR Gene
Adenosine Deaminase
Alpha Adducin
Gamma Adducin
Adrenomedullin
Adenosine A2 Receptor
Beta Adrenergic Receptor
MANY, MANY MORE (116)
Rare Diseases (e.g. Cystic Fibrosis) are due to changes in single genes
Common diseases (e.g. Hypertension) result from changes in multiple genes that have small effects in isolation but can lead to disease when interacting with one another and the environment

6. So, what Is the Minimum that a clinician needs to know About Genetic Testing?

7. Deciphering the FDA Clopidogrel Black Box Warning
Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.

8. 1. What is CYP2C19 and what are we measuring?
CYP2C19 = gene
We typically measure a SNP (single nucleotide polymorphism) within the gene

9. What is a SNP? Single-Nucleotide Polymorphism
CYP2C19
Example: 85% of population has major allele G rs
Poor Metabolizers
15% has minor allele A
From Wikipedia Commons, David Hall (Granger)

10. Marker SNPs & Causal SNPs
Haplotype Blocks
Blocks of DNA tend to stay together throughout recombination
Linkage
A nucleotide on same block of DNA can be used as a marker
Linkage analysis; Wellcome Trust Website 20/3/03. Richard Twyman
Ardie et al. Nature Reviews, 3, (April 2002)

11. Spectrum of Clinical Genetic Testing
Rare Mutation Testing
Test for rare mutations in single genes associated with rare diseases; sequence gene for mutation
Common Polymorphism Testing (SNP)
Test for SNPs/markers in genes with small individual effects associated with common diseases
Sequencing Entire Genome/Exome
Clinics Today
Future Clinical

12. SNPs in Candidate Genes
Patient in Cath Lab, use 25ul blood, get point of care test results in 60 minutes
<$50

13. Genome Wide Association Studies (GWAS)
$200
Measure 2 million SNPs across genome
Can now look at copy number variation, etc
Christensen and Murray, NEJM, 2007

14. Advances in Genome Sequencing
Sanger Method
$3,000,000,000/ genome
Step-Over” Repeated Segments of DNA
Sequence short fragments in parallel fashion
Reassemble short sequenced fragments
Use Physical Location to id unique reads
Next Generation Sequencing
$5,000/genome

15. Exome Sequencing
$1500
Exons are the genomic DNA parts translated into protein
180,000 exons: about 1% of the human genome = 30 (Mb)
Constitute about 85% of the disease-causing mutations
From: Wikipedia Commons, Sarah Kusala
Exome Sequencing

16. Whole Genome Sequencing
$5000
(intentionally left small)

17. Epigenome

18. Thank you

19. Additional slides

20. Types of Genetic Changes
Coding vs. Non Coding
Causal variant vs. marker
Types of genetic changes
Polymorphisms
Mutations
structural variants
tissue-specific epigenetic
DNA methylation, histone modifications, and chromatin state

21. How SNPs are measured
Schematic showing blood to tube to cells to DNA to sequence to machine

23. Currently useful tests

24. Definitions: Mutation vs. Polymorphism
Mutation: <1% of time
Often has functional effects
Polymorphism: >1% of time
Define SNP