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

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

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

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

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

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

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 25000 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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