Pharmacogenomics 2024 PDF

Challenges to curing diseases big problem Non-scientific factors Lack of drugs to treat diseases 1 Ex : ppl with L some religious belief which...

Challenges to curing diseases big problem Non-scientific factors Lack of drugs to treat diseases 1 Ex : ppl with L some religious belief which drugs can candidate , work well w anim preventthem from taking Challenges medication or vaccination L✗ for humans I Drugs cause toxicity Drugs don’t work for some people for everyone  Challenges to curing diseases The reasons for Lack of drugs to treat diseases? important rtlumanbiologyx understood well Mechanisms of diseases not understood – Basic science - Small molecule drugs are not a viable option for many diseases – Protein and gene therapy Orphan diseases – NIH support lrarediseasethatnoora.li#efundingreceivedtocure. Clinical trial failures - ? lbig challenge  Phases of clinical trial Basic science (decades) 7 Preclinical research (few years) Ltestw animal 10– 15 years and $1 billion later – one → successful drug. 90% or more drug candidates fail!!  Why clinical trials fail? Clinical trial failures Drugs don’t work Toxic side effects L some of them ✗ Work well in humans Multiple reasons Random pick Wrong population? ✓ ppl not screened & for specificfeatures  Variability in drug response Fava beans Hemolytic anemia Pythagoras guise 9 …individuals respond differently to medications lack of efficacy { due to adverse drug reactions/toxicity  Variation in drug response We want to minimize the variability L what is good for average population Source: Peck, RW (2018) Annu. Rev. Pharmacol. Toxicol. 58:105. Fig. 1 Other protein have binding pocket for same drug → cause side effect Variability in drug response less efficacy if Having gene variant → less responsivetoadrug → glowthedrugaffectsyourbody What governs efficacy and toxicity of the drug (Pharmacodynamics drugs? rdeterminewhy reduced rhowbodyaffect Pharmacokinetics efficacy n¥icity Receptors Enzymes Absorption efficacyI ⑧Metabolism " → Lsomeppl Lxweeeafgeot binds well Ion channels ↳ drug "Distribution (✗Excretion weeez ifagrouphaveenzyme slightly deviant different toxicity , toxins ↳ xworkwellforthoseppe Drugs cause [ Efficacy tforthoseppl orsideeffectinthoseppl ifdrugxbindwell receptor  Why would PD & PK vary? inherent to determines p Intrinsic factors how you respond to autsidefactors Extrinsic factors age important : drug-drug interactions weight (body mass index) diet/nutritional status sex alcohol/drug abuse pregnancy/lactation smoking organ function/dysfunction environmental toxicants comorbidities medication or disease : medical (e.g., med errors, non- epigenetics (e.g.,present in human DNA methylation) body compliance) microbiome GENETICS L influence respond to drug  The role of genotype in phenotype determination Flower color alleles: P = purple dominant both pair of chromosomes have same allele p = white recessive Homozygous Homozygous: Both : pair of chromosomes have the same allele. Different Heterozygous: alleles Different alleles Heterozygous: 1 2 Mendelian Mendelian ratio: 1:2:1 ratio : : : I Genes – the units of heredity 23 pair Terminologies : Chromosomes, Diploid, autosomes, genes 122  Are human diseases caused by genes? Genetic disease genetic environment t mutation lcombination of genetic & environment Virtually all human diseases, except perhaps trauma, have a genetic component. Source: https://www.ncbi.nlm.nih.gov/books/NBK20363/  Are human diseases caused by genes? chromosomes present in both sexes type Mendelian Inheritance: Autosomal Dominant plheno J your in if mutation is present showing up → variant gene (mutation) = Have mutation dominant allele to have disease only one copy of the variant gene needs to be present to express the phenotype examples: Huntington’s Disease, hypercholesterolemia B the replace safest way is to all the the TRS genes except & then put human gene in that place.  Are human diseases caused by genes? Mendelian Inheritance: Autosomal Recessive iflcopyismutatedyitxaffectbecauseother J is dominant variant gene (mutation) = recessive two copies of the variant gene needed to express the phenotype examples: cystic fibrosis, sickle-cell disease, others  Are human diseases caused by genes? Mendelian Inheritance: X-linked Dominant have mutation shave - Lmutationinx disease chromosome variant gene (mutation) = dominant 0 \ examples: fragile X syndrome  Are human diseases caused by genes? Mendelian Inheritance: X-linked Recessive Male has 1 ✗ chromosome → still have disease female has 1 ✗ variant → ✗ affect by disease ✗ mutation gene (mutation) = o !ñ%o recessive nisi examples: glucose 6- 8 phosphate dehydrogenase deficiency; hemophilia A, B  Are human diseases caused by genes? ✗ common r Mendelian Disorders: variations in single-genes (monogenic) occur in families with a pattern that reflects the inheritance of a single causative gene. Complex Disorders: common human diseases involving multiple genes (polygenic) Examples: L Most common hypertension, obesity, type 2 diabetes, cardiovascular disease, mental disorders (autism, schizophrenia), Alzheimer’s disease However, many diseases are not regulated by a single gene. However, knowing those genes would still be useful for improving treatment.  Why would PD & PK vary? Intrinsic factors Extrinsic factors age drug-drug interactions weight (body mass index) diet/nutritional status sex alcohol/drug abuse pregnancy/lactation smoking organ function/dysfunction environmental toxicants comorbidities medical (e.g., med errors, non- epigenetics (e.g., DNA methylation) compliance) microbiome twins twinw dizygotic if havingGENETICS , compare monozygotic Pharmacokinetic [ Does genetics influence PD & PK? r Lpharmacodynamic  I role have identical Genetic plays a in monozygotic twins genome ↳ metabolism is similar L genetic contributing pharmacokinetic to  What is pharmacogenomics? variability of toxicity of drug efficacy of p determine or pharmacogenomics – the role genes and genetic variants play in determining how a person responds to drugs drug intersection of: pharmacology – science of drugs and their actions genomics – structure, function, evolution, and regulation of the genome still an emerging field  Goals of pharmacogenomics? PGx aims: to predict how a patient will respond to a drug (phenotype) based on their genetic make-up (genotype) 4 major uses of PGx information: select right drug optimize the dose minimize adverse drug reactions (ADRs)/toxicity guide new drug development l clinical trial clinical goal: devise individualized drug treatment strategies that maximize therapeutic benefit and minimize the risk of adverse drug reactions or toxicity (personalized medicine)  Goals of pharmacogenomics same diagnosis, same treatment toxicity high efficacy ← fdrugworkwellduetominimal - much toxicity iliitleaffect No effect ftp.ctatoxicity - ( much toxicity Source: Adams et al. (2018) Clin. J. Am. Soc. Nephrol. 13:1561. Fig 1 27  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  Pharmacokinetic & pharmacodynamics mechanisms Warfarin (anticoagulant/blood thinner) Sources of variable No need response to warfarin for exam warfarin 0 response to variability dueto 1- mutation ]  Pharmacodynamics mechanisms Adverse drug reaction Type A Type B Unrelated to known Related to the drug effect drug’s effect L side (immunologically effect mediated ADR) Type B: Stevens-Johnson syndrome and toxic necrolysis (SJS/TEN) SJS is less severe than TEN. Different degrees of skin detachment. SJS less than 10% of the body, TEN >30%, SJS/TEN – 10-30% Multiple medications, including antiseizure drug carbamazepine, NSAIDs, can trigger SJS/TEN in some people Abacavir, an anti HIV drug, also elicit drug hypersensitivity in some people.  Pharmacodynamics mechanisms Immunological ADR was found to be dependent on the HLA alleles L human tosurveytcdl p leukocyte to present antigen of protein " ✗ attack taheyourpart oraetivate virus ↳ immune } system ✓ Major histocompatibility complex Ltakevival outs MHC Class I: HLA-A, -B, protein present and -C present short peptides - ↳ Tcellalert from inside the cell ← activate immune includes “self” peptides and system those from pathogens (e.g., bacteria, viruses) Mutation happens immune reaction I activate immune T system ingestion whentakesomedru.gl/-cellthinks1hat's /^ ↳ changed properties  Pharmacodynamics mechanisms Enriched in pforgout : Anti seizure drug https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525617/  Somatic mosaicism mutation affect mutated germ cell germ cell Genes 2014, 5(4), 1064-1094; https://doi.org/10.3390/genes5041064  Somatic mosaicism Child still affected i : Father has mutated cell w lo disease germ  Somatic mosaicism mutation - still cell division in 1 part of body → generated Every mitotic cell division is associated with certain frequency of mutations. oflarger part  Cancer pharmacogenomics Cancer cells undergo multiple mitotic divisions and accumulate mutations. Treatments can be tailored based on cancer specific mutations. However, inherited variations should also be considered. cancer drug cancercell may good for ✗ ppl but should treat for cancer cells. 1 mutation  Cancer pharmacogenomics Cancer mutations Prognostic markers Predictive markers (markers indicating the (markers useful for course or the outcome identifying patients who are of the disease) likely to respond to a drug.) t Cancers 2020, 12(11), 3234;  Cancer pharmacogenomics Prognostic markers (markers indicating the course or the outcome of the disease) associated w breastcancer p BRCA1 and BRCA2 are genes that produce proteins that repair damaged DNA. They act as tumor suppressors Lw lo BRCA mutation Similarly, mutations in Glutathione-s-transferase increases prostate cancer risk and those in the APC gene increases polyps and tumors in the gut.  Cancer pharmacogenomics Predictive markers (markers useful for identifying patients who are likely to respond to a drug) r by cancer 's growthfactor Ctoo many) Blocking epidermal growth factor receptor (EGFR) suppresses tumor growth. But KRAS mutations in codon 12 and 13 activates KRAS independent of EGFR and blocking EGFR does not help! treatment Cetuximab and panitumumab don’t work with KRAS mutations  Epigenome ADME genes Genes encoding proteins for drug absorption, distribution, metabolism, and excretion Mutations in these genes are responsible for pharmacokinetic variations but it only accounts for a small fraction. CYP2C1 hypomethylation – Parkinson’s disease CYP1A, CYP1B methylation – prostate cancer CYP2W1 methylation – colon cancer  Geography of an individual ryrpartlyresponsetodrug ~10% of diseases gene expression MA T protein sequence on DNA chemical modification expofurelevel tovarious toxin LMRI body imaging scan