Pharmacogenomics 2024 PDF

Goals of pharmacogenomics with classify ppl based on genetic variation → come...

Goals of pharmacogenomics with classify ppl based on genetic variation → come the up best drug PGx-Guided Treatment best dosage test genetic Variation between pple ( certain group differently @ genetic Vari I # - ✗fit respond normally drug ( dueto to Source: Adams et al. (2018) Clin. J. Am. Soc. Nephrol. 13:1561. ✗ absorbed ( Fig 1 ✗ clear with the drug t 28 well well drug regular dosage  LI source come from DNA%ombi nation chromo ingermcells some Anychangesfromourbody →✗ goto next-generation orrecombinationingene only mutations Llchromomatics Lproduoespermsoregge I recombine ✗ Goto lion next-generation Mix byyouroww have previous + new rrlextgeneration : DNA sequence ⑧ from unique sperm w Lmixematclrfrompwrentalchromosal  more chance to get disease How variation in DNA emerges in population? 1 More divide spermatogonia rlothappeninmom ↳ more producer> moreehance of mutation spermSpermatogonia w g§Éɧ Mitosis product sperm d 8 oooo oo Meiosis ¥08 §§$° 8 Sperm roriginatedingermcellofdad 30 mutations per sperm Somatic mutations don’t go the next generation  How variation in DNA emerges in population? Dad Mom Kid 1 Kid 2 The first level of emergence of DNA variation in the population Due to germline mutations, kids will have DNA variation compared to their parents. new rsamegenew Mutations generates variations in a gene (alleles) different V mutations ✗ altmutations spread The physical location in population of alleles on the DNA is referred to as loci  How variation in DNA emerges in population? Dad Mom What is a population? Kid 1 Kid 2 Mutation -> alleles But not all mutations (or group of individuals defined by alleles) will spread in the shared characteristics – e.g., social, cultural, religious, population to similar extent. historical, geographic, disease phenotype RIZA alleles rmajorallelerminor Major allele: The most If 6 people have AA, 3 have AB and 1 - common allele of population have BB, then 15 A allele and 5 B - Minor alleles: All other alleles. A allele freq : 15/20 and B allele freq: 5/20  ④ 2① 6 ppl : AA → 12A alleles 3 ppl AB : → & 3 B alleles BB Apple : → population } 15A : Freq A: 15120 45£ : B : 5120 total : 20 alleles What decide what alleles have spread in population ? How we variation thatcontinent ① Natural selection allele is selected because in their existence : L [ it give survival when a reproductive alleles when the mutation favor 1st step spreading in population Mix with neanderthal reproduce with neanderthal → mixed genes : random ② when alleles due to Genetic drift : disappear pure no reason L No natural selection. L no reproductive and population ✗ survive decides which alleles in population present. ③ Gene flow : whenever alleles transferred from 1 population to another How variation in DNA emerges in population? 1 original Mutation & Natural evolved selection - family Mix with neanderthal Genetic drift Gene flow 2 Individuals in every 3 region continues to Genetic accumulate drift mutations but only some may spread in Gene the population flow  How variation in DNA emerges in population? 1 2 3 May physically identify with the ‘green’ race but the reality is more complicated Most alleles are present in all populations. Recent alleles (rare variants) are more specific to a population  How variation in DNA emerges in population? High variable low variable Two alleles: A and a Skin pigmentation AA Aa aa Within continents: 10% Population 1 A 10 40 ¥40 10 20 Between continents: 90% the alleles Population 2 10 25 5 much more than population Genetic differences within a population is greater than that between populations.  Population Allele Frequencies r involved in metabolism what drug *1 and *2 = normal enzyme activity if you wantto decide on [ *3, *4, *5, *6 = no enzyme activity to give you , want to dosage know genetics 38 Knowing the geographical ancestry rather than ”race” is more precise for understanding the biology of an individual  How many DNA variants are present in humans? How big is our genome and haploid genome: 3.055 billion how many genes do we have? base pairs 1-2% encodes proteins (exomes) 98-99% non-coding DNA once called “junk” DNA many functional RNAs (mRNA, non-coding RNAs) 2019: 46,932 transcripts structural and regulatory functions 1 in 1000 base pair is different between any two individuals. ~3 million single nucleotide variants per individual  DNA variations and medicine Entire haploid Genome (3 billion base pairs) Genes A chromosome and genes DNA variations can be seen all over the genome and only a small fraction will be on the genes. If we map the DNA variations in the genome, it will help us with ) Identifying genes involved in disease or drug response 2) As a diagnostic tool to group people based on their drug response (even without knowing the genes involved).  What are the different types of DNA variations? Most common Single Nucleotide Variant (SNV) I most common (>90%) type of genetic variation also known as single nucleotide polymorphism (SNP, pronounced “snip”). SNV is preferred term; SNP if > 1% frequency. ( ① =] - identical nucleotide 42 only different in single What are the different types of DNA variations? Minor allele frequency (MAF): how often the less common allele occurs in a population MAF descriptors: ✗ Common = >0.05 (>5%) Low = 0.01-0.05 (1-5%) Rare = 120 genetic variants identified (2018 data) metabolizes ~25% of all prescribed drugs i CYPZDG (t) antidepressants (amitriptyline, fluoxetine) antipsychotics (chlorpromazine) analgesics (codeine) antihypertensives (carvedilol) estrogen receptor antagonist (tamoxifen)  Pharmacokinetic mechanisms Cyp2D6 Codeine Morphine CYP2D6 Allele Description Enzyme Phenotype Activity *1, *2, *33, *35 Normal Normal EM *9, *10, *17, *41 Reduced Decreased IM function ~, ↳ Tdosage *3, *4, *5, *6 Null No protein or PM mutations give Nonsense inactive → otherdrug *22, *37, *45, *55 Unknown Unknown ?? *1xN, *2xN Duplicated Increased ludosageUM PM = poor metabolizer, IM = intermediate metabolizer, EM = extensive metabolizer, UM = ultra-rapid metabolizer Source: Hoskins et al. (2009) Nat. Rev. Cancer 9:576. Table 1  Pharmacokinetic mechanisms CPIC Guidelines: CYP2D6/Codeine CYP2D6 Example Codeine Metabolism Recommendation Phenoty diplotypes (abridged) pe PM *4/*4, *4/*5, greatly reduced morphine insufficient pain relief; (5-10%) *5/*5, *4/*6 formation avoid codeine use IM *4/*10, *5/*41 reduced morphine follow label dosing; if no (2-11%) formation response, consider alternative analgesic EM *1/*1,*1/*2,*2/* normal morphine follow label dosing (77-92%) 2,*1/*41,*1/*4,* formation 2/*5,*1/*10 UM *1xN, *2xN greatly increased potential for toxicity; (1-2%) morphine formation avoid codeine use PM = poor metabolizer, IM = intermediate metabolizer, EM = extensive metabolizer, UM = ultrarapid metabolizer.  Pharmacokinetic mechanisms Enzyme Active Inactive metabolite drug If the metabolism of active drug is dependent on a single enzyme (or a single major enzyme) and the drug has narrow therapeutic window then genetic variation will have a large cYP2D6:y impact excessive W1ocYP2D6 : ↳ Nortriptyline T CYP2D 6 6 Bag 410-hydroxyl nortriptyline (tricyclic antidepressant) 25mg nortriptyline CPIC recommends to avoid nortriptyline for ultrarapid metabolizers and very poor metabolizers. Reduced dosing for poor metabolizers.  Pharmacokinetic mechanisms knowing alleles variations → ability to do Pharma cogmeino But not mean certain genotype give specific Complexities of CYP2D6 PGx Testing phenotype drug metabolism and CYP2D6 genotype extensively studied inferring a patient’s metabolic capacity (phenotype) from CYP2D6 genetic testing is not straightforward :X mean full inform to treat patient >120 variants CYP2D6 genotype panels include only most common alleles drug rare variants never tested :-) Never know how they metabolite any given patient may carry alleles not tested for substantial variation in term phenotype between individuals with the same apparent genotype ofCYP2176 ↳ both patient has same " identical but genotype different metabolism level. 87 other things > who we are Genetic + ( metabolism,.. :)  Pharmacokinetic mechanisms CYP2D6 Activity Varies Within Genotypes identical ÷ 0 - genotype t alone genetics ✗ givefull inform Source: Gaedigk, A. (2013) Intl. Rev. Psychiatry 25:534. Fig. 1B (subjects of European ancestry) I give partial inform  Pharmacokinetic mechanisms would genetics alone not be sufficient ? Why Possible Explanations CYP2D6 protein content varies between patients with nominally identical genotypes. genetic plus non-genetic factors microbes ✓ environment, epigenetic , inflammation (e.g., HIV, HCV decrease CYP2D6 expression) drug-drug or drug-botanical interactions changes in intestinal microbiome  Pharmacokinetic mechanisms Enzyme Active Inactive metabolite drug r enzyme killing TPMT 6-methyl mercaptopurine white (inactive) blood cancer cells Thiopurines (e.g., azathioprine, 6-mercaptopurine) cytotoxic, immunosuppressive agents also kill WBCS : acute lymphocytic leukemia (ALL), inflammatory bowel disease (IBD; off-label), renal transplantation narrow therapeutic index (high-risk PK)  Pharmacokinetic mechanisms Enzyme Active Inactive metabolite drug Transporters Active Elimination from circulation drug Simvastatin Transporter Elimination from circulation elimination poor - i respond to statin % change LDL-C 8 0 0 SLCO1B1*5 allele – loss of function of 156 patients given 40, 80, or → transporter. Not 160 mg/d eliminated – 9 simvastatin x 6 Efficacy wk with 2-wk increased myopathy target washout between treatments eliminated drug well  Pharmacokinetic mechanisms > Active drug give different or drug Enzyme vs dosage : opposite direction i. givetdoesage igivetdosage > inactive T drug > giver dosage Enzymevsdosagedirection : same igivetdosage