My Research: Pharmacogenomics

Discovery of regulatory genetic variants in genomics and pharmacogenomics

Sadee has led a systematic effort to discover regulatory variants in critical genes affecting disease and treatment outcomes, using genomics databases and experimental procedures. He has employed early on the use of allelic RNA expression imbalance as a powerful tool to detect cis-acting regulatory variants affecting transcription, RNA processing and functions, and translation. Key publications include the following:

Single nucleotide polymorphisms in the human  opioid receptor gene alter G protein coupling and calmodulin binding.  D. Wang, J.M.Quillan, K. Winans, J.L. Lucas, W. Sadée.  J.Biol.Chem. 276: 34624-34630 (2001).

The potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. K.A. Phillips, D.L. Veenstra, E. Oren, K. Lee, W. Sadée.  J.Amer. Med. Assn., 286: 2270-2279 (2001).

A semi-automated approach to gene discovery through EST data mining: Discovery of new human transporter genes S. Brown, J.L. Chang, W. Sadée, P.C. Babbitt. AAPS PharmSci, 5(1): article 1 (2003). http://www.aapspharmsci.org/ps0501/ps050101/ps050101.pdf.

Membrane Transporters and Channels: Role of the Transportome in Cancer Chemosensitivity and Chemoresistance. Y. Huang, P. Anderle, K.J. Bussey, C. Barbacioru, U. Shankavaram, Z. Dai, W. C. Reinhold, A. Papp, J. N. Weinstein, W. Sadée. Cancer Res. 64:4294-4301 (2004).  DOI: 10.1158/0008-5472.CAN-03-3884

Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics. Johnson AD, Wang D, Sadée W.  Pharmacol.Ther.  106:19-38 (2005).

Cystine/glutamate transporter SLC7A11 in cancer chemosensitivity and -resistance. Y. Huang , Z. Dai, C. Barbacioru, W. Sadée.  Cancer Res. 65: 7446-7454 (2005).

Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G.  Y. Zhang, D. Wang, A.D. Johnson, A.C. Papp, W. Sadée. J.Biol.Chem. 280: 32618-32624 (2005).

Allellic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR. J.-E. Lim, A. Papp, j. Pinsonneault, W. Sadée, D. Saffen.    Molec.Psychiatry 11:649-62 (2006).

Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C (CACNA1C) in human heart tissues. D. Wang, A.C. Papp, P.F. Binkley, J.A. Johnson, W. Sadée. Pharmacogen.Genomics 16: 735-745 (2006).

Allelic mRNA expression of X-linked monoamine oxidase A (MAOA) in human brain: Dissec killer). Z. Dai, S. Liu; G. Marcucci, W. Sadee.  BBRC 351: 455-461 (2006).

Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. J.-E. Lim, J. Pinsonneault J, W. Sadee, D. Saffen.  Molec.Psychiatry, 12: 491-501 (2007).

Chemogenomics of sensitivity and resistance to anticancer drugs.  Z. Dai, W. Sadee, P. Blower.  Curr.Pharmacogenom. 5: 11-19 (2007).

Chemoinformatics analysis identifies cytotoxic compounds susceptible to chemoresistance mediated by glutathione and cystine/glutamate transport system Z. Dai, Y. Huang, W. Sadee, P. Blower.  J.Med.Chem. 15: 1896-1906 (2007).

Novel polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.  Y. Zhang, A. Bertolino, L. Fazio, G. Blasi, A. Rampino, R. Romano, Mei-L.T. Lee, T. Xiao , A. Papp, D. Wang, W. Sadée.  Proc.Natl.Acad.Sci.USA. 104: 20552-20557 (2007). (Selected by Faculty of 1000 Biology)

Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues.  A.D. Johnson, Y. Zhang, A.C. Papp, J.K. Pinsonneault, J.-E. Lim, D. Saffen, Z. Dai, D. Wang, W. Sadée.  Pharmacogen. Genom. 18: 781-791 (2008).

Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement.  D. Wang, H. Chen, K.M. Momary, L.H. Cavallari, J.A. Johnson, W. Sadée.  Blood 112: 1013-1021 (2008).

Promoter polymorphisms in ACE (angiotensin-I converting enzyme) associated with clinical outcomes in hypertension.  A.D. Johnson, Y. Gong, D. Wang, T.Y. Langaee, J. Shin, R.M. Cooper-DeHoff, N.J. Schork, P. Binkley, C.J. Pepine, J.A. Johnson, W. Sadee.  Clin.Pharmacol.Ther,  85: 36-44 (2009).

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans. G. Blasi, L. L. Bianco, P. Taurisano, B. Gelao, R. Romano, L. Fazio, A. Papazacharias, A. Di Giorgio, G. Caforio, A. Rampino, R. Masellis, A Papp, G. Ursini, L. Sinibaldi, T. Popolizio, W. Sadee, A. Bertolino.  J. Neurosci. 29: 14812-14819 (2009).

Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. D. Wang, Y. Guo, S.A. Wrighton, G.E. Cooke, W. Sadee. Pharmacogenomics J 11: 274-286 (2011). PMID 20386561

Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse.  R.A. Moyer, D. Wang, A.C. Papp, R.M. Smith, L. Duque, D.C. Mash, and W. Sadee.   Neuropsychopharm. 19: 76-83 (2011). PMCID: PMC3055737

Pharmacogenomics of the RNA World: Structural RNA polymorphisms (srSNPs) in drug therapy.  W. Sadee, D. Wang, A.C. Papp, J.K. Pinsonneault, R.M. Smith, R.A. Moyer, and A.D. Johnson.  Clin.Pharmacol.Ther. 89:355-365 (2011).

Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder.  J.K. Pinsonneault, D.D. Han, K.E. Burdick, M. Kataki, A. Bertolino, A.K. Malhotra, H.H. Gu, W Sadee.  Neuropsychopharmacology 8: 1644-1655 (2011); doi: 10.1038/npp.2011.45. PMCID: PMC3138671

man N-acetyltransferase 1 (NAT1) *10 and *11 alleles increase protein expression via distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.  D. Wang, M.F. Para, S.L. Koletar, W. Sadee.  Pharmacogenetics Genomics, 21: 652-664 (2011). DOI: 10.1097/FPC.0b013e3283498ee9.

Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.  A.C. Papp, J.K. Pinsonneault, D. Wang, L.C. Newman, Y. Gong, J.A. Johnson, C. J. Pepine, M. Kumari, A.D Hingorani, P.J. Talmud, S. Shah, S.E Humphries, and W. Sadee.  PLoS ONE, 7(3): e31930. doi:10.1371 (2012).

mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention.  E.S. Barrie, R.M. Smith, J.C. Sanford, W. Sadee.  Molec.Pharmacol. 81: 620-630  (2012)  doi:10.1124.  PMID 22319206

Sadee. Relevance of ‘missing heritability’ in pharmacogenomics. Clin.Pharmacol.Ther. 92: 428-430 (2012). doi: 10.1038/clpt.2012.116.  PMID:22910439.   PMC3638892

R.M. Smith, A.C. Papp, A. Webb, C.L. Ruble, L.M. Munsie, L.K. Nisenbaum, J.E. Kleinman, B.K. Lipska, W. Sadee.  Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex.  Biol. Psych.  73: 546-554 (2013).  DOI: 10.1016. PMID 22825450.

Webb, A.C. Papp, K. Huang, J.D. Parvin, W. Sadee. Expression of mRNA transcripts encoding membrane transporters detected with whole transcriptome sequencing of human brain and liver. Pharmacogen.Genom. 23: 269-278 (2013) PMID:23492907.

Wang, M.J. Poi, X. Sun, A. Gaedigk, J.S. Leeder, W. Sadee. Common CYP2D6 Polymorphisms Affecting Alternative Splicing and Transcription: Long-range Haplotypes with Two Regulatory Variants Modulate CYP2D6 Activity. Hum.Mol.Gen.  23: 268-278 (2014).  PMID:23985325.

W. Sadee, K. Hartmann, M. Seweryn, M. Pietrzak, S.K. Handelman, G.A. Rempala. Missing heritability of common diseases and treatments outside the protein-coding exome. Hum.Gen. 133: 1199-1215 (2014). PMID: 25107510.

E.S. Barrie, D. Weinshenker, A. Verma, S.A. Pendergrass, L.A. Lange, M.D. Ritchie, J.G. Wilson, H. Kuivaniemi, G. Tromp, D.J. Carey, G.S. Gerhard, MH. Brilliant, S.J. Hebbring, J.F. Cubells, J.K. Pinsonneault, G.J. Norman, W. Sadee.  Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity.  Circ.Res.  115: 1017-1025 (2014).   PMID: 25326128

Mascarenhas, M. Pietrzak, R.M. Smith, A. Webb, D. Wang, A.C. Papp, J.K. Pinsonneault, M. Seweryn, G. Rempala, W. Sadee. Allele-selective transcriptome recruitment to polysomes primed for translation: protein-coding and noncoding RNAs, and RNA isoform. PLoS One, 10(9): e0136798 (2015).  DOI: 10.1371/journal.pone.0136798

J.C. Sanford, X. Wang, E. Stofko Barrie, D. Wang, H-J Zhu, W. Sadee, Regulatory effects of genomic translocations at the human carboxylesterase-1 (CES1) gene locus.  Pharmacogen. Genomics,  Febr.11 (2016).  PMID: 2687123

E.S. Barrie, K. Hartmann, S.-H. Lee, J.T. Frater, M. Seweryn, D. Wang, W. Sadee.  The CHRNA5/CHRNA3/CHRNB4 nicotinic receptor regulome:  genomic architecture, regulatory variants, and clinical associations.  Human Mutation 38:112-119 (2017).  PMID:27758088,  doi: 10.1002/humu.23135

Li, L. Zhang, P.F. Binkley, W. Sadee, D. Wang. Regulatory variants modulate protein kinase C α (PRKCA) gene expression in human heart. Pharm.Res. 34:1615-1625 (2017) PMID: 28120175.

A.M. Suhy, A. Webb, A.C. Papp, E.G. Geier, W. Sadee.  Expression and Splicing of ABC and SLC Transporters in the Human Blood-Brain Barrier Measured with RNAseq.  Europ.J.Pharm.Sci.  103: 47-51 (2017). http://dx.doi.org/10.1016/j.ejps.2017.02.010  PMID: 28188910

J.K. Pinsonneault, J. Frater, B.Kompa, R. Mascarenhas, D. Wang, W. Sadee. Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits.  PLoS ONE 12(6):e0179020. doi: 10.1371/journal.pone.0179020. (2017).  pone.0179020. eCollection 2017

Wang, MD, K Hartmann, M. Seweryn, W. Sadee. Interaction between regulatory variants in CYP7A1 (cholesterol 7-hydroxlase) promoter and enhancer regions regulates CYP7A1 expression. Circulation Genom.Precis.Med. CIRCGEN.118.002082 (2018).  PMID: 30354296

Ray B, Ozcagli E, Sadee W, Wang D. CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele): implications for CYP2D6 genotyping panels.  Pharmacogen. Genom. 29: 39-47 (2019) doi: 10.1097/FPC.0000000000000363.

Wang, R., Lu, G. Rempala, W. Sadee. Ligand-Free Estrogen Receptor Alpha (ESR1) as Master Regulator for the Expression of CYP3A4 and other Cytochrome P450s (CYPs) in Human Liver. Mol.Pharm. 96: 330-340 (2019) DOI: https://doi.org/10.1124/mol.119.116897; PMID:31399483

K. Hartman, M. Seweryn, W. Sadee.  Interpreting coronary artery disease GWAS results: A functional genomics approach assessing biological significance.  PLoS ONE 17(2): e0244904. (2022) https://doi.org/10.1371/journal.pone.0244904  (BioRxiv.  EMID:3bc9e3488dd6340c (2020). PLoS ONE, in press (2022)