1. Personalized Medicine
Mohammad Al-Hamad Al-Zoubi, PhD
Assistant professor, Department of Pathology
Section Head of Cytogenetics and Molecular Laboratories
University of Dammam
Personalized medicine has already changed the lives of hundreds of thousands of people, and is well on its way to changing the lives of millions.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

2. Concept of Personalized Medicine
Personalized medicine is about delivering to the right individual the right care at the right time in the right place.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

3. Is the Idea of personalized medicine new?
Hippocrates: It’s more important to know what sort of person has a disease than to know what sort of sort of disease a person has.
Personalized medicine is getting lot of press and people are very interested in the Idea that their medicine should personalized, but the fact that we take care of patient in very highly individualized way is not something new.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

4. Is the Idea of personalized medicine new?
Sir William Osler:
“The good physician treats the disease; the great physician treats the patient who has the disease”.
More recently sir william Osler the father of modern medicine is widely quoted
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

5. what is so special about this vogue for personalized medicine?
We know forever that occasional patients seem different from the average somehow.
The excitement in personalized medicine is that we now have new tools with which to understand the variability and to exploit it.
How susceptible or resistant they are to disease?
How well they’ll or how badly they will respond to drug?
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

6. Understand the DNA Molecule can change the medicine
The advent of advanced molecular techniques like NGS participate greatly in our understanding of DNA molecule. With knowledge about the structure of genome and biology of genome one can start to study and understand the biology of disease, and then can imagine starting the change in medicine.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

7. Human Karyotype v Total: 3 billion base pairs (2X) 25000 genes
247M bases
2815 Genes
242M bases
1860 Genes
199M bases
1497 Genes
191M bases
1136 Genes
180M bases
1276 Genes v
Total: 3 billion base pairs (2X)
25000 genes
170M bases
1575 Genes
158M bases
1512 Genes
146M bases
1013 Genes
140M bases
1245 Genes
135M bases
1105 Genes
134M bases
1850 Genes
132M bases
1370 Genes
It turns out that the longest chromosome is chromosome 1 it has 247 million base pairs that encode around 2815 genes
Most of the molecule is occupied by non-coding DNA and that non-coding DNA serves a regulator function. It tells when gene should be turned on, and turned off in specific cell types.
So the total is shown in the slide here and I am not going to go through each chromosome, you can read it.
But the total is 3 billion base pairs per 23 chromosomes so 6 billion base pairs per 46 chromosomes in Human cell and around genes.
114M bases
545 Genes
106M bases
1315 Genes
100M bases
998 Genes
88M bases
1098 Genes
78M bases
1494 Genes
76M bases
429 Genes
X: 154M bases
1376 Genes
63M bases
1743 Genes
62M bases
768 Genes
46M bases
360 Genes
49M bases
749 Genes
Y: 57M bases
284 Genes
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

8. We are not the same we are 99.9% the same and 0.1 variation
If the DNA sequences in each cell in each person on the face of the planet were exactly the same, then we should all look the same, and we would all have very similar susceptibility to disease, we would have very similar response to drug.
Keep in mind (notice) that I am not saying its Identical because a lot of our susceptibility to disease and to drug responses might be to non-genetic factors.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

9. Variants of DNA molecules
DNA Variants
No Effect
Natural variations, eyes
Hair color
Serious consequences
There are lots of DNA variants in the DNA molecule that we are beginning to understand now, some of the variants occur at the level of chromosome and some of them occur at the level nucleotide base pairs.
Sometimes that variation does not mean anything; sometimes it causes natural variation such as the differences we see in eyes color and hair color.
Response to drug
Susceptibility
to disease
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

10. Types of Polymorphisms
Single Nucleotide Polymorphism (SNP)
Copy Number Variant (CNV)
Polymorphism is an area of DNA sequence that varies from person to person.
Types of polymorphisms:
1. SNP is a polymorphism in which a single base in the DNA sequence differs from the usual base at that position.
2. “Copy number variant” (CNV) – a polymorphism in which the number of repeats of a DNA sequence at a location varies from person to person
3. a polymorphism in which a DNA sequence is either present (insertion) or absent (deletion) at a location, varying from person to person
“Indel” Polymorphism
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

11. Most Drug-metabolizing enzymes exhibit clinically relevant Genetic polymorphisms
Drugs are metabolized by specific enzymes in the liver, and each drug has its own enzyme or enzymes, that accomplished its metabolism to other drug metabolites, usually more hydrophilic than the parent drug that allows the drug to be excreted by the kidney and bile.
Drug metabolism is traditionally divided into 2 parts
Phase I drug metabolism is process of drug oxidation, hydroxylation that is accomplished by members of the cytochrome p450 superfamily, we abbreviate that CYP, such as CYP2c9…. So each one of those enzymes metabolizes one or more drugs that are important for human therapeutics.
Phase II does not affect the structure of the drug, it attaches new molecule to the drug such as acetyl group methyl group sulfonyl group. The enzymes that accomplish that are called transferase.
So those are the enzymes that accomplish drug metabolism. The important point is that each one of these has genetic variants in the gene that encodes the particular enzyme that you are looking at. And these variants may be important for variable drug metabolism and that in turn can affect response to drug. So that’s one of the way the genetics affect the drug response.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

12. Warfarin a good candidate for personalized medicine
Widely prescribed anticoagulant
Narrow therapeutic index.
Proper warfarin dosing is challenging due to variations in the genes of
CYP2C9
VKORC1
Warfarin is used broadly in patients with atrial fibrillation, heart valve replacement, recent heart attack, and for venous thromboembolism prophylaxis in patients who
have undergone hip or knee replacements.
However,
warfarin has a narrow therapeutic range: at low doses it does not decrease the risk of stroke, while at higher
doses it significantly increases the risk of intracranial bleeding.
which impact the clinical efficacy of the medication
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

13. Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

14. Functionally important CYP2C9 Variants
Caucasians 12%
Caucasians 5%
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

15. CYP2C9 Variants: Warfarin Dose and bleeding Events
< than 3mg/day
Clinical Controls
5mg/day
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018
Aithal etal., Lancet 1999

16. Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

17. The Warfarin Pathway
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

18. Variants in the promoter of VKORC1
90%
42%
80%
60%
VKORC1 3673
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

19. CYP2C9, VKORC1: Warfarin Dose
KFHU
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

20. Conclusion:
The contribution of VKORC1 variation in dose requirement is larger (approximately 30%) than the contribution of CYP2C9 (usually less than 10%).
Individuals who are most likely to benefit from genetic testing are those who have yet to start warfarin therapy.
Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

21. The story
continue…..
Laboratory Medicine: Current Aspects and Future prospects
2/27/2018

22. Thank you Laboratory Medicine: Current Aspects and Future prospects
2/27/2018