Pharmacogenomics In Psychiatry Wolfgang Sadee OSU Program in Pharmacogenomics The Ohio State University XGEN Group NIH PGRN
Why do we need biomarkers in drug therapy? Limited efficacy Adverse drug effects Genetic factors: drug metabolizing enzymes! J Amer Med Assn, 286:2270-2279, 2001 FDA CDER: Valid Genomic Biomarkers for Approved Drug Labels http://www.fda.gov/cder/genomics/genomic_biomarkers_table.htm
Why do we need improved therapies? Poor efficacy Response Rates (%) 80% 80 70 60% 60 50 40% 40 30 20% 20 10 0% 0 Depression Schizophrennia Oncology Alzheimer's Incontinence HCV Osteoporosis Migraine (prophylaxis) Rheumatoid Arthritis Migraine (acute) Diabetes Asthma Cardiac arrythmias Schizophrenia Depression (SSRI) Analgesics (Cox2) From Brian Spear, Abbott
Drug Link in Drugs@FDA Therapeutic Area Biomarker Label Sections with Pharmacogenomic Information Abacavir Antivirals HLA-B*5701 Boxed Warning, Contraindications Warnings and Precautions Patient Counseling Carbamazepine Neurology HLA-B*1502 Boxed Warning Cetuximab Oncology EGFR KRAS Indications and Usage Warnings and Precautions Indications and Usage Clopidogrel Cardiovascular CYP2C19 Boxed Warning Dasatinib Oncology Ph Chromosome Indications and Usage Doxepin Psychiatry CYP2D6 Precautions Imatinib Oncology C-KIT, PH Chrom., PDGFR, FIP1L1- PDGFRa Indications and Usage Maraviroc Antivirals CCR5 Warnings and Precautions Tamoxifen Oncology ER Indications and Usage Trastuzumab Oncology Her-NEU Indications and Usage FDA CDER: Valid Genomic Biomarkers for Approved Drug Labels http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
FDA CDER: Valid Genomic Biomarkers for Approved Drug Labels 2010 CYP2D6 EM, PM fluoxetine, atomoxetine, venlafaxine, risperidone, olanzepine, clozepine, aripiprazol, codeine CYP2C19 EM, PM diazepam HLA-B*1502 carbamazepine, phenytoin Urea Cycle Disorder valproic acid (UCD) Deficiency* *hyperammonaemic encephalopathy, ornithine transcarbamylase (OTC) deficiency, carnitine deficiency, cerebral mitochondrial dysfunction http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
GWAS of carbamazepine-induced cutaneous ADRs (53 Japanese patients and 882 controls) Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Ozeki T et al. Hum Mol Genet. 20:1034-1041 (2011).
DRUG METABOLISM GENETICS Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics William E. Evans, Mary V. Relling Science 286:487 (1999) http://www.sciencemag.org/cgi/content/full/286/5439/487/f2
Antidepressants and Antipsychotics Mostly lipophilic drugs that require P450 metabolism Cytochrome P450 poor metabolizers Ethnic differences CYP2D6 : 5-10% PM Caucasian, 1-3% Orientals CYP2C19: ~20% PM Orientals, 3-5% Caucasians Drug Substrates CYP2D6 : chlorpromazine, haloperidol, risperidol CYP2D6+CYP2C19: fluoxetine, nortriptyline (consider drug-drug interactions plus genotype Tanaka and Hisawa, J.Clin.Phamacol.Ther. 24: 7-16 (1999)
Why are PGx tests not used in Psychiatry? Which tests are clinically useful? Who is already using them? What are the costs?
CYP2D6 GENOTYPE-PHENOTYPE RELATIONSHIP Doxepine Genotype or or or or Phenotype ULTRARAPID METABOLIZERS EXTENSIVE METABOLIZERS INTERMEDIATE METABOLIZERS POOR METABOLIZERS Frequency (Caucasians) 5 10 % 80 65 % 10 15 % 5 10 % dose requirement number of patients 90 80 70 60 50 40 30 20 10 0 MR=12.6 0.01 0.1 1 10 100 higher usual dose lower MR Meyer U.A., Nat Rev Genet 2004
Variability in PK - CYP2D6 and doxepin Kirchheiner et al Pharmacogenetics & Genomics 15:579-587, 2005 120 Doxepin [nmol/l] 100 80 60 40 20 0 PM n=9 IM n=8 EM n=14 UM n=6 P < 0.001, ANOVA 0 20 40 60 80 hours Pharmacogenetics 2002; 12: 571-580
CYP2D6-based dose adjustments for antidepressants and antipsychotics % dose adjustment of a standard dose 200 150 100 50 0 Imipramine Doxepin Maprotiline Trimipramine Desipramine Nortriptyline Clomipramine Paroxetine Venlafaxine Amitriptyline Mianserin Perphenazine Zuclopenthixol Thioridazine Aripiprazole Flupentixol Haloperidol Perazine Risperidone Ultrarapid Extensive Intermediate Poor metabolizer Mol Psychiatry 2004; 9: 442-473
Bottleneck: finding functional genetic variants Regulatory polymorphisms prevalent Driving evolution?? Disease models, drug response??
Regulatory polymorphisms studied by XGEN at OSUMC Gene Function Variant location mechanism ABDB1/MDR1 transporter synonymous mrna turnover NAT1 metabolism 3 UTR polyadenylation, translation CYP2C9 metabolism ~ -1kb promoter transcription CYP3A4 metabolism intron6 RNA elongation? CYP2D6 metabolism Exon, enhancer Splicing, expression DAT dopamine transporter intron8, 3 UTR mrna processing, translation DRD2 dopamine receptor intron5,6 ~ -1kb enhancer splicing transcription OPRM1 opioid receptor nonsynonymous RNA processing, translation CHNRA5 nicotine ~ -15kb enhancer transcription HTR2A serotonin receptor ~ -1kb promoter transcription MAOA serotonin metabolism 3 -UTR?? TPH2 Serotonin synthesis Exon8 splicing VKORC1 cardiovascular ~ -1kb promoter transcription ACE hypertension ~ -3K enhancer transcription CETP cardiovascular intron8/exon9 ~ -5kb enhancer splicing transcription
CYP3A4 expression in human livers Gen.Eng.News 21:29 (2001) Epidauros Biotechnologie. Bernried, Germany
CYP3A4 *22 allele rs35599367 Intron 6 SNP (3-8% allele frequency) affects expression 2-5 fold Decreases statin dose requirements Wang et al. TPJ 2011 Wang et al., Pharmacogenomics J. 11: 274-286 (2011)
Dopamine and Serotonin Signaling Drug Targets: DRD2 and 5HT2A Antidepressants Atypical antipsychotics TPH2 MAOA Cocaine: DRD2 + DAT VMAT2 VMAT2 5HTR2A D2S and DAT COMT
Alternative splicing of the D2 dopamine receptor rs1076560 rs2283265 DRD2 gene locus E8 E6 encodes 29 AA in 3 rd cytoplasmic loop 65.5 kb E1 short (D2S): presynaptic (inhibitory); long (D2L): postsynaptic (facilitative) Intronic SNPs reduce D2S expression; multiple clinical phenotypes Zang et al. PNAS 2008
fmri study in normal adults during memory task Activation of striatal pathways by intronic DRD2 SNP Collaboration Alessandro Bertolino, University of Bari, Italy (PNAS 2007; Brain 2008; J. Neurosci. 2009)) SNP i6
Dopamine Transporter Julie Pinsonneault (npp 2011) SLC6A3 gene structure Exon 1 4 8 12 15 52.6 Kb 5/6 repeat rs6350 Exon 2 rs464049 rs6347 Exon 14 rs37022 rs1042098 & rs11564774 rs27072 Exon 15 rs1809939 rs3797200 3 VNTR Possibly 3 functional variants Impact on mrna expression in SN Association with bipolar disorder No significant effect on cocaine abuse/death
Dopamine signaling and lethal cocaine abuse DRD2-DAT: Gene-gene-environment interaction in cocaine abuse DAT-DRD2 SNP combination: risk OR 7-8 Sullivan et al. EPISTASIS + Drug effect
Next Generation Sequencing Core lab director Audrey Papp X X X X X X X X X X X X G A G A A A G A A G A G A A Whole Genome Whole transcriptome Noncoding RNAs RNA trafficking (CLIP) Allelic RNA expression Splicing Polyadenylation sites Transcription sites Antisense RNAs
HTR2A 5 UTR Expression promoter SNP alters TIS and translation efficiency rs6313: CT ~ 23 rs1328685: CT ~ 27 R. Smith submitted
Pharmacogenomics implementation at OSUMC NIH Pharmacogenomics Research Network (TPP project, Peter Embi) Establish biomarker assays (CLIA) Store data safely prospective Transfer data to emrs Present flags upon drug prescription Provide background data link Example: clopidogrel and CYP2C19 Next generation sequencing
Gene-Environment Interactions: from wellness to disease - a hypothesis Frequent variants affect disease risk, symptoms, and drug response contingent upon environmental factors Environment Life style, behavior frequent variants affect normal traits Genes Epigenetics rare variants are deleterious wellness off-well illness disease