Table 1 Functional polymorphisms identified by XGEN group, Center for Pharmacogenomics in OSU College of Medicine.

Transcription

1 Table 1 Functional polymorphisms identified by XGEN group, Center for Pharmacogenomics in OSU College of Medicine. Gene Functional polymorphisms or haplotypes identified Functions of polymorphisms or haplotypes and underlying mechanisms Association studies references OPRM1 mu opioid receptor rs (A118G, N40D) SNP allele changes OPRM1 RNA folding and decreases mrna expression and protein translation (1) ABCB1 multidrug resistance gene 1, MDR1 rs (3435 C>T, *13) SNP allele changes ABCB1 RNA folding and decreases ABCB1 mrna stability (2) TPH2 tryptophan hydroxylase isoform 2 DRD2 dopamine receptor subtype 2 ACE angiotensin I- converting enzyme Haplotype containing rs , rs , rs , rs , rs Two highly linked intronic SNPs rs and rs , and one promoter SNP (rs ) Three highly linked promoter SNPs rs , rs , rs4290 Haplotype containing A allele of rs increases TPH2 mrna levels, possibly by affecting TPH2 exon7 splicing Minor alleles of both intronic SNPs affect DRD2 exon6 alter splicing to D2 short and long, and promoter SNP increases DRD2 mrna transcription Minor SNP alleles are associated with decreased ACE mrna transcription in the heart Intronic SNPs are associated with altered memory processing measured with fmri in normal individuals and schizophrenia patients. Minor alleles associated with increased risk of adverse cardiovascular outcomes with odds ratio of 6.16 ( ) (3) (4) (5) (6)

2 VKORC1 vitamin K epoxide reductase complex subunit 1 CYP3A4 cytochrome P450 3A4 CHRNA5 nicotinic α5 receptor subunit DAT Dopamine transport Promoter SNP rs (-1639 G>A) Intronic SNP rs (C>T) Six highly linked enhancer SNPs >>10 kb upstream: rs , rs , rs , rs880395, rs and rs UTR SNP rs27072 Minor allele generates a suppressor E-box binding site, affecting histone modification, decreasing VKORC1 mrna expression Minor allele decreased CYP3A4 mrna level and CYP3A4 enzyme activity in human livers, possibly via changing RNA folding, affecting nascent RNA elongation Minor alleles of these SNPs increased CHRNA5 mrna transcription Minor allele reduced mrna expression, possibly via microrna regulation Minor allele associated with lower warfarin dose and is better predictor for warfarin dosing than intron2 SNP 1542 G>C in African Americans. Minor allele associated with lower dose requirement of CYP3A4 metabolized statins (atorvastatin, lovastatin and simvastatin) in patients with cardiovascular disease. After adjusting for nonsynonymous SNP rs , minor alleles of these SNPs were associated with a 22% increased risk of developing nicotine dependence rs27072 is associated with increased risk of bipolar disease (7) (8)(9) (10) (11)(12) NAT1 N-acetyltransferase 1 CETP Cholesteryl ester transfer protein NAT1*10 (rs ) and NAT1*11 (rs , rs , rs , rs and a nine-base pair deletion in 3 UTR rs Promoter/enhancer SNP rs247616, and exon 9 SNP rs5883 NAT1*10 increased translation efficiency, while NAT1*11 increased NAT1 mrna via changing 3 -polyadenylation site usage Promoter SNP rs decreased CETP transcription, while exon 9 SNP rs5883 affect exon 9 splicing NAT1*10 and *11 are associated with sulfamethoxazole-induced hypersensitivity Both SNPs are associated with increased HDL-C levels in male, and in a different rs5883 (13) (14)

3 is associated with increased incidence of MI, stroke and allcause mortality in males. HTR2A 5-hydroxytryptamine 2A receptor SP-A Surfactant protein Promoter SNP rs6311 and 3 UTR SNP rs (unique to African descent Intronic SNP rs rs6311 decreased usage of a upstream transcription start site encoding a longer 5 UTR with greater translation efficiency, while rs modulate mrna expression Affect SP-A mrna expression via affecting splicing rs6311 in combination with another previously reported SNP rs6314 is associated with depression severity (15) (16) CYP2D6 Cytochrome P450 2D6 Exon 6 SNP rs16947 (*2) and enhancer SNPs rs /rs rs16947 reduced CYP2D6 mrna expression via affecting exon 6 splicing, while enhancer SNP rs /rs increased transcription via long-range enhancer-promoter interactions Combination of rs16947 and enhancer SNP determine CYP2D6 mrna expression and enzyme activity (17) References: (1) Y. Zhang, D. Wang, J.D. Andrew, A.C. Papp and W. Sadée. Allelic expression imbalance of mu opioid receptor (OPRM1) caused by variant A118G. J. Biol. Chem. 280: , 2005, PMID (2) D. Wang, D.J. Andrew, A.C. Papp, D.L. Kroetz and W. Sadée. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mrna stability. Pharmacogenetics and Genomics, 15: , 2005, PMID (3) J-E. Lim, J. Pinsonneault, W. Sadee and D. Saffen. Tryptophan hydroxylase 2 (TPH2) haplotype predict levels of TPH2 mrna expression in human pons. Mol. Psychi. 12(5): , 2007 (4) Y. Zhang, A. Bertolino, L. Fazio, G. Blast, A. Rampino, R. Romano, M.L.T. Lee, T. Xiao, A. Papp, D. Wang and W. Sadee. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc. Natl. Acad. Sci. USA 104: , 2007 PMID

4 (5). A. Bertolino, L. Fazio, G. Caforio, G. Blasi, A. Rampino, R. Romano, AD. Giorgio, P. Taurisano, A. Papp, J. Pinsonneault, D. Wang, M. Nardini, T. Popolizio and W. Sadee. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain, 132: , PMID (6) AD. Johnson, Y. Gong, D. Wang, TY. Langaee, J. Shin, RM. Cooper-Dehoff, NJ. Schork, P. Binkley, CJ. Pepine,JA. Johnson, W. Sadee. Promoter polymorphisms in ACE (Agiotension I converting enzyme) associated with clinical outcomes in hypertension. Clinical Pharmacology and Therapeutics, 85:36-44, PMID (7) D. Wang, H. Chen, K. M. Momary, L. H. Cavallari, J. A. Johnson and W. Sadee. Regulatory polymorphism in vitamin K epoxide reductase subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 112: , 2008 PMID (8) D. Wang, Y. Guo, S.A. Wrighton, G.E. Cooke and W. Sadee. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. The Pharmacogenomics J. 11(4): , 2011, PMID (9) J. P. Kitzmiller, D. M. Sullivan, M. A. Phelps, D. Wang and W. Sadee. CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control. Drug Metabolism and Drug Interactions 28(1): 59-63, 2013, PMID (10) R.M., Smith, H. Alachkar, A.C. Papp, D. Wang, D.C. Mash, J. Wang, L.J. Bierut and W. Sadee. Nicotinic alpha receptor subunit mrna expression is associated with distant 5 upstream polymorphisms. Eur. J. Human Mol. Gen. 19(1):76-83, 2011, PMID (11) J. K. Pinsonneault, D. D. Han, K. E. Burdick, M. Kataki, A. Bertolion, A. K. Malhotra, H. H. Gu and W. Sadee. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36: , 2011, PMID (12) D. Sullivan, J.K. Pinsonneault, A.C. Papp, H. Zhu, S. Lemeshow, D.C. Mash and W. Sadee. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene environment interaction. Translational psychiatry 3:e222, 2013, PMID (13) D. Wang, M.F. Para, S. L. Koletar and W. Sadee. Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associated with sulfamethoxazole-induced hypersensitivity. Pharmacogenetics and Genomics 21: , 2011, PMID (14) 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. Talmus, S. Shah, S. E. Humphries and W. Sadee. Cholesteryl ester transfer protein (CETP) polymorphisms affect mrna splicing, HDL levels and sex-dependent cardiovascular risk. PlosOne 7(3): e31930, 2012, PMID (15) R. M. Smith, A. C. Papp, A. Webb, C. L. Ruble, L. M. Munsie, L. K. Nisenbaum, J. E. Kleinman, B. K. Lipska and W. Sadee. Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex. Biol Psychiatry 73: , 2013, PMID

5 (16) A. K Azad, A. Curtis, A.C. Papp, A. Webb, D. Knoell, W. Sadee and L. S. Schlesinger. Allelic mrna expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene. Genes Immun. 14(2): , 2013 (17) D. Wang, M. J. Poi, X. Sun, A. Gaedigk, J.S. Leeder and W. Sadee. Common CYP2D6 polymorphisms affecting alternative splicing and transcription: Long haplotype with two regulatory variants modulate CYP2D6 activity. Human Molecular Genetics, 2013 Sep4 [Epub ahead of print], PMID