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Using genetics for drug prescribing: will it happen? • Hype and hope • Relating DNA polymorphisms to variable human physiology and drug responses: examples • A view to the future Take-home messages • Diversity among human genomes can explain variability in human physiology, and its response to the environment. • Pharmacogenetic information is now affecting drug development, and will enter clinical practice (a personal opinion). • “Proving” genotype-phenotype relations requires collaborations among clinical investigators, basic biologists, information managers and statisticians, systems biologists, technologists, ethicists… Case presentations • Grade 4 diarrhea occurs in a 65 year old man receiving irinotecan for colon cancer. • A 70 year old woman starts coumadin 5 mg/day for atrial fibrillation. One week later, her INR is 12. • A 78 year man develops a QT interval of 700 msec and Torsades de Pointes a day after starting dofetilide. • Life-threatening sepsis arises in a 9-year-old girl after 6-MP therapy for ALL. • A 68 year old man presents with a large anterior myocardial infarction, and has a VF arrest in the Emergency Room. Pharmacogenetics: Large single gene effects “idiosyncratic” drug response understand the biology identify causative DNA variants “idiosyncratic” response now predictable and avoidable 6-thioguanines (6-TGNs) azathioprine cytotoxic “single nucleotide polymorphisms” (SNPs) *1/*3A *1/*1 6-TGN concentrations 1/300 *3A/*3A HH HL LL *1/*1 *1/*3A *3A/*3A (mutant) (heterozygote) (wild-type) An “idiosyncratic” drug response AR, 78 year old man • Chronic heart disease with history of bypass surgery and valve replacement • Cardiac arrest 4 days after major abdominal surgery; placed on dofetilide (a potent and highly selective blocker of a potassium current called IKr) to prevent recurrence. 2 days later: Torsades de Pointes • Also characteristic of the congenital long QT syndrome • Drug-induced QT prolongation and torsades is the single commonest cause for drug withdrawal or relabeling in the past decade. AR: An “idiosyncratic” drug response • DNA variant resulting in R583C identified in KCNQ1, a gene controlling QT duration and mutated in a common form of the congenital Long QT Syndrome. • R583C alters protein function in vitro: reduces IKs. • Absent in >1000 controls “mutation”. This man has the congenital long QT syndrome, that remained asymptomatic for 78 years. How did AR avoid arrhythmias for 2,000,000,000 heart beats? The concept of reduced repolarization reserve • Redundancy (“reserve”) in cardiac repolarization allowed him to maintain a normal QT until other lesions (heart disease, dofetilide) were superimposed. Patient 1 Patient 2 Same QT-prolonging drug Redundancy in physiologic systems: “high risk pharmacokinetics” low margin between doses needed for efficacy and doses producing toxicity (therapeutic index) PLUS a single pathway for drug elimination that is genetically variable or subject to inhibition by interacting drugs Drug A Drug B Drug C Drug D TPMT CYP2C9 transport by drug efflux pump CYP3A4 inactive metabolite 6-MP inactive metabolite warfarin inhibitor drug renal excretion digoxin inhibitor drug inactive metabolite terfenadine (Seldane) Redundancy in physiologic systems: “high risk pharmacokinetics” TPMT Drug A CYP2C9 Drug B Drug C transport by drug efflux pump Drug D CYP3A4 inactive metabolite 6-MP inactive metabolite warfarin inhibitor drug renal excretion digoxin inhibitor drug inactive metabolite terfenadine (Seldane) Drug E CYP2C9 transporter CYP3A4 TPMT inactive metabolite renal excretion inactive metabolite inactive metabolite Drug E will be an especially attractive agent if it also has a high therapeutic index Redundancy in physiologic systems as a protective mechanism • arrhythmia susceptibility • susceptibility to adverse drug reactions and interactions • “multi-hit” requirement for carcinogenesis Pharmacogenetics: Large single gene effects “idiosyncratic” drug response Pharmacogenomics: Discovering new biology unusually variable drug response understand the biology identify associated DNA polymorphisms identify causative DNA variants “idiosyncratic” response now predictable and avoidable 1950 • adjust dose or change drugs • discover new biology and new drug targets 1980 2020 PHARMACOGENOMICS Smaller effect; multiple variants Large single variant effect PHARMACOGENETICS Single gene Small number of genes Complex biologic pathway Whole genome PHARMACOGENOMICS Smaller effect; multiple variants Large single variant effect (large populations) PHARMACOGENETICS (snlall groups) Single gene • • • • Small number of genes Complex biologic pathway Whole genome Rare coding region variants (polymorphisms or mutations) Commoner coding and regulatory variants Detectible effects of polymorphisms in >1 gene Pathway analysis and whole genome approaches Variants in the warfarin target Variants in the warfarin target – 2 Single Nucleotide Polymorphisms (SNPs) in the VKORC1 promoter C CG A TC T C T G T G CGC Reider et al. 25 = 32 possible combinations NEJM 2005 Haplotype A: CCGATCTCTG Haplotype B: TCGGTCCGCG Variants in both drug metabolism (CYP2C9) and drug target (VKORC1) genes affect warfarin dose requirement Reider et al., NEJM 2005 • 554 patients on chronic warfarin; early dropouts not included • CYP2C9 genotype predicts 9% of dosage variability • VKORC1 haplotype accounts for 23% • Illustrates • Multi-gene effects can be detected • Understanding mechanisms in rare syndromes can inform the study of common biologic problems • Increasing importance of haplotypes A 68 year old man presents with a large MI, and has a VF arrest in the ER Patient 1 Patient 2 Same acute MI ?“reduced antifibrillatory reserve” Reduced cardiac sodium current predisposes to serious arrhythmias Sodium channel blocking drugs increase mortality % survival Placebo (n=725) encainide or flecainide (n=730) Loss of function mutations in the sodium channel gene cause a distinctive ECG and ↑↑risk of VF Brugada syndrome Days from randomization Hypothesis: Variable sodium channel expression is a candidate mechanism for variability in basal conduction velocity, and in susceptibility to slowed conduction with exogenous stressors (drugs, myocardial ischemia). Slow conduction predisposes to sudden death due to VF. 6 sodium channel promoter variants, found only in Asians C287T G-354C -835insGC T-847G T-1062C T-1418C 6 variants: 26 = 64 possible combinations promoter intron 1 exon 1 (non-coding) -2000 bp -1000 0 1000 6 sodium channel promoter variants, found only in Asians, in very tight linkage disequilibrium T T T --- G C 75.5% Haplotype B C C G ins C T 24% Haplotype C C T T --- C C 0.5% T-847G -835insGC G-354C C287T T-1418C Haplotype A T-1062C Frequency* Frequency promoter intron 1 exon 1 (non-coding) -2000 bp -1000 0 1000 Haplotype B ↓↓promoter activity Fold activity 18 CHO cells 15 Cardiomyocytes n=13, p=0.04 n=9, p=0.006 12 9 6 3 0 A B Wild Type 6-change haplotype A Wild Type B 6-change haplotype Ventricular conduction is slower with the reduction of function allele QRS duration (msec) 140 120 normals 100 80 60 34 AA AB 8 BB 140 120 100 45 21 5 AA AB BB 80 71 probands with Brugada Syndrome Genotype-dependent incremental conduction slowing by sodium channel blockers 200 QRS duration (msec) +20 msec +17 msec +29 msec AA AB BB 160 120 80 Who has the longest QRS duration? Brugada Syndrome mutation + drug exposure + BB haplotype “Genes load the gun, environment pulls the trigger” Pharmacogenetics: Large single gene effects “idiosyncratic” drug response Pharmacogenomics: Discovering new biology unusually variable drug response understand the biology identify associated DNA polymorphisms identify causative DNA variants “idiosyncratic” response now predictable and avoidable 1950 • adjust dose or change drugs • discover new biology and new drug targets 1980 2020 The future Moving to widespread practice Routine patient visit identify or look up DNA variants in that patient adjust dose or change drugs 2050 Nature Oct. 5, 2005 Genotypes: CYP2D6: CYP2C9: NAT: TPMT: UGT1A1: ACE: CETP: BRCA1: b1 AR: b2 AR: KCNQ1: HERG: KCNE1: KCNE2: Apoe: ABCA1: *4/*4 wt/*2 slow wt/wt 6/6 ID BB negative S49/G389 R16/G27 R583C wt/wt wt/wt wt/wt 2/3 wt/wt Genotypes: CYP2D6: CYP2C9: NAT: TPMT: UGT1A1: ACE: CETP: BRCA1: b1 AR: b2 AR: KCNQ1: HERG: KCNE1: KCNE2: Apoe: ABCA1: *4/*4 wt/*2 slow wt/wt 6/6 ID BB negative S49/G389 R16/G27 R583C wt/wt wt/wt wt/wt 2/3 wt/wt