Pharmacogenomics and Targeted Therapy in Patient Care
- 1. Pharmacogenomics and Targeted Therapy in Patient Care Wolfgang Sadee OSU Program in Pharmacogenomics The Ohio State University XGEN
- 2. Limited efficacy Adverse drug effects Genetic factors: J Amer Med Assn, 286:2270-2279, 2001 Why do we need genetic biomarkers in drug therapy?
- 3. Bottleneck: finding functional genetic variants Regulatory polymorphisms prevalent Driving evolution??
- 4. Types of functional polymorphisms noncoding RNAs
- 5. From basic research to clinical studies CYP3A4 main drug metabolizing enzyme (Wang, TPJ, 2010) ABCB1 (MDR1), CYP2C9, CYP2C19, NAT1 (D. Wang) ACE hypertension, myocardial infarction (CPT, 2009) CETP main drug target in cholesterol control (in preparation) VKORC1 warfarin dosing (Blood, 2008) TPH2 serotonin levels in brain (Mol. Psych, 2006) DRD2 cognition, schizophrenia, addiction (PNAS, 2007, Brain 2008, J. Neurosci.2009) DAT and MAOA (Julie Pinsonneault); SERT (JE Lim, Mol.Psych. 2007) CHNRA5 and 5HT2A (R. Smith, 2010); OPRM1 (Y. Zhang, JBC 2007)
- 6. PGx genotyping and dose adjustments Kirchheiner, Fuhr & Brockmöller Nature Rev/Drug Disc 4, 639-647, 2005 CYP2B6 CYP2C9 VKORC1 CYP2D6 CYP2C19 TPMT NAT2 Missing: CYP3A4
- 7. CYP3A4 expression in human livers Gen.Eng.News 21:29 (2001) Epidauros Biotechnologie. Bernried, Germany Genetic and/or environmental causes for CYP3A4 variability ?? CYP2D6 test comprehensive?? Do current PGx test account for all/most Genetic causes of variability ?
- 8. CYP3A4 Intronic SNP (4-8% allele frequency) affects expression 2-5 fold Decreases statin dose requirements Wang et al. TPJ 2010 singleton : does not tag anything (positive selection?) Missed by GWAS
- 9. D2 dopamine receptor ( DRD2 ) Main component of dopamine signaling Target of anti-schizophrenic drugs Key factor in drug addiction Splicing: D2S and D2L ratios in dopamine signaling Ying Zhang PNAS 104: 20552 (2007)
- 10. DRD2 splice variants: distinct functions Marker SNPs splicing short: presynaptic (inhibitory) long: postsynaptic (facilitative) Intronic SNPs Promoter SNP PNAS 2007, Brain 2008, J. Neurosci. 2009
- 11. DRD2 splice variants: interaction with cocaine rs2283265 association with cocaine abuse P=0.001, OR 3.33 (1.42-7.80) (n=~200) Moyer et al. (submitted) Gene-gene interactions (epistasis): DRD2 – DAT Dopamine Transporter Possibly 3 functional variants Impact on mRNA expression in SN DRD2 – DAT in cocaine abuse: DAT SNPs protective Association with bipolar disorder OR ~2 Pinsonneault et al., to be submitted
- 12. Regulatory polymorphisms abundant in candidate genes Importance of using functional variants Gene-gene interactions: Model for human health/disease/therapy Guide selection of optimal therapy: Efficacy Adverse effects
- 13. Expression Genetics via Next Generation Sequencing Whole Genome Whole transcriptome Noncoding RNAs RNA trafficking (CLIP) Allelic mRNA expression Splicing Polyadenylation sites Transcription sites Antisense RNAs A G G G G G A A A A A A A A X X X X X X X X X X X X
- 14. Sadee/PGx Lab: Ryan Smith Leslie Newman Collaborators: Julie Johnson Danxin Wang Audrey Papp Danielle Sullivan Phil Binkley David Saffen Julia Pinsonneault Beth Barrie Gloria Smith Anil Malhotra Anke Hilse van der Zee Robert Moyer Jonathan Sanford Andrew Johnson Deborah Mash Alessandro Bertolino
Editor's Notes
- #14: Billions of reads of short sequence. But, what are we sequencing, and what can we expect from the results?