Precision Medicine into Clinical Practice: A Web-Based Tool Enables Real-Time Pharmacogenetic Assessment of Tailored Treatments in Psychiatric Disorders
Abstract
:1. Introduction
2. Materials and Methods
2.1. Selection of Drugs and CYP Variants
2.2. DNA Purification and Quantification
2.3. OpenArray™ Technology
2.4. Statistical Analysis
2.5. NeuroPGx Software Designing
2.6. NeuroPGx Software Application
3. Results
4. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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GENEs | HGVS | Alleles 1 | Major Nucleotide Variation | RS ID | AssayID | Nucleotide Change | Effect on Protein |
---|---|---|---|---|---|---|---|
CYP2B6 | NC_000019; NG_007929.1; NM_000767; NP_000758.1 | *22, *34, *35, *36 | −82T > C | rs34223104 | C__27830964_10 | g.40991224T > C | Upstream Transcript Variant |
*16, *18 | 983T > C | rs28399499 | C__60732328_20 | c.983T > C | p.Ile328Thr | ||
*5, *7 | 25505C > T | rs3211371 | C__30634242_40 | c.1459C > T | p.Arg487Cys | ||
CYP2C19 | NC_000010; NG_055436; NM_000769; NP_000760 | *17 | −806C > T | rs12248560 | C____469857_10 | −806C > T | Upstream Transcript Variant |
*4A/B | 1A > G | rs28399504 | C__30634136_10 | c.1A > G | p.Met1Leu | ||
*8 | 12711T > C | rs41291556 | C__30634130_30 | c.358T > C | p.Trp120Arg | ||
*6 | 12748G > A | rs72552267 | C__27531918_10 | c.395G > A | p.Arg132Gln | ||
*9 | 12784G > A | rs17884712 | C__25745302_30 | c.431G > A | p.Arg144His | ||
*3 | 17948G > A | rs4986893 | C__27861809_10 | c.636G > A | p.Trp212Ter | ||
*10 | 19153C > T | rs6413438 | C__30634128_10 | 19153C > T | p.Pro227Leu | ||
*2 | 19154G > A | rs4244285 | C__25986767_70 | c.681G > A/19154G > A | p.Pro227 = | ||
*7 | 19294T > A | rs72558186 | C__30634127_10 | g.94781999T > A | Splice Donor Variant | ||
*5 | 90033C > T | rs56337013 | C__27861810_10 | c.1297C > T | p.Arg433Trp | ||
CYP2C9 | NC_000010; NG_008385; NM_000771; NP_000762 | *2, *35, *61 | 3608C > T | rs1799853 | C__25625805_10 | c.430C > T | p.Arg144Cys |
*6 | 10601delA | rs9332131; hcv32287221 | C__32287221_20 | c.818delA | p.Lys273ArgfsTer34 | ||
*11 | 42542C > T | rs28371685 | C__30634132_70 | c.1003C > T | p.Arg335Trp | ||
*3, *18 | 42614A > C | rs1057910 | C__27104892_10 | c.1075A > G | p.Ile359Val | ||
*4 | 42615T > C | rs56165452 | C__30634131_20 | c.1076T > C | p.Ile359Thr | ||
*5 | 42619C > G | rs28371686 | C__27859817_40 | c.1080C > G | p.Asp360Glu | ||
CYP2D6 | NC_000022.11; NG_008376; NM_001025161; NP_000097 | *10, *36, *37, *47, *49, *52, *54, *57, *64, *65, *69, *72, *87, *94, *95, *99, *100, *101, *114, *132 | 100C > T | rs1065852 | C__11484460_40 | c.100C > T | p.Pro34Ser |
*12 | 124G > A | rs5030862 | C__27531552_A0 | c.124G > A | P.Gly42Arg | ||
*17, *40, *58, *64, *82 | 1022C > T/A | rs28371706 | C___2222771_A0 | c.320C > T; c.320C > A | p.Thr107Ile; p.Thr107Asn | ||
*6 | 1708delT | rs5030655 | C__32407243_20 | c.454delT | p.Trp152GlyfsTer2 | ||
*8, *14, *114 | 1759G > A/T | rs5030865 | C_30634117D_M0/C_30634117C_K0 | c.505G > T;c.505G > C; c.505G > A | p.Gly169Ter; p.Gly169Arg; p.Gly169Arg | ||
*4 | 1847G > A | rs3892097 | C__27102431_D0 | c.506-1G > A | Upstream Transcript Variant | ||
*3 | 2550delA | rs35742686 | C__32407232_50 | c.775delA | p.Arg259GlyfsTer2 | ||
*7 | 2936A > C | rs5030867 | C__32388575_A0 | c.971A > C | p.His324Pro | ||
*32, *41, *69, *91, *119, *123, *132, *138 | 2989G > A | rs28371725 | C__34816116_20 | c.985+39G > A | Intron Variant | ||
*29, *70, *109 | 3184G > A | rs59421388 | C__34816113_20 | c.1012G > A | p.Val338Met | ||
*2, *8, *10, *11, *12, *14, *17, *19, *20, *21, *28, *29, *30, *31, *32, *35, *36, *37, *39, *40, *41, *42, *45, *46, *47, *49, *51, *52, *54, *55, *56, *57, *58, *59, *64, *65, *69, *70, *72, *73, *83, *84, *85, *87, *88, *94, *95, *98, *99, *100, *101, *102, *103, *104, *105, *111, *114, *117, *121, *123, *125, *126, *128, *129, *132, *133, *135, *136, *138 | 4181G > C | rs1135840 | C__27102414_10 | c.1457C > G | p.Thr486Ser | ||
*2, *8, *11, *12, *14, *17, *19, *20, *21, *28, *29, *30, *31, *32, *34, *35, *40, *41, *42, *45, *46, *51, *55, *58, *59, *65, *69, *73, *84, *85, *91, *98, *102, *103, *104, *105, *111, *114, *117, *121, *123, *125, *126, *128, *129, *133, *135, *136, *138 | 2851C > T | rs16947 | C__27102425_10 | c.886T > C | p.Cys296Arg | ||
*9, *109, *115 | 2616delAAG | rs5030656; HCV32407229 | C__32407229_60 | c.841_843delAAG | p.Lys281del | ||
CYP3A5 | NC_000007.14; NG_007938; NM_000777; NP_000768 | *8 | 3699C > T | rs55817950 | C__30633872_10 | c.82C > T | p.Arg28Cys |
*3 | 6986A > G | rs776746 | C__26201809_30 | c.−253-1G > A | Downstream Transcript Variant | ||
*3 | 6986A > G + H30Y (3705C > T) | rs776746; rs28383468 | C__30633871_50 | c.88C > T | p.His30Tyr | ||
*6 | 14690G > A | rs10264272 | C__30203950_10 | c.624G > A | p.Lys208 = | ||
*9 | 19386G > A | rs28383479 | C__30633863_10 | c.1009G > A | p.Ala337Thr | ||
*7 | 27131_27132insT | rs41303343 | C__32287188_10 | c.1035dupT | p.Thr346TyrfsTer3 | ||
*2 | 27289C > A | rs28365083 | C__30633862_10 | c.1193C > A | p.Thr398Asn |
Drug | Genes 1 | References |
---|---|---|
Agomelatine | CYP1A2, CYP2C9 | [10,11] |
Alprazolam | CYP2C19, CYP2C9, CYP3A4, CYP3A5, CYP3A7 | [10,12,13,14] |
Amitriptyline | CYP2D6, CYP2C19, CYP1A2, CYP2C9, CYP3A4 | [10,15] |
Aripiprazole | CYP2D6, CYP3A4 | [10,16,17] |
Atomoxetine | CYP2D6, CYP2C19 | [18,19] |
Bupropion | CYP2B6 | [10,15] |
Buspirone | CYP3A4 | [10,20] |
Carbamazepine | CYP1A2, CYP3A4, CYP3A5, CYP2C19, CYP2C8 | [10,21,22,23] |
Chlorpromazine | CYP2D6, CYP2C19, CYP1A2, CYP3A4 | [10,24,25,26] |
Citalopram | CYP2C19, CYP2D6, CYP3A4 | [10,15,27] |
Clobazam | CYP2C19, CYP3A, CYP2B6 | [28] |
Clomipramine | CYP2D6, CYP2C19, CYP1A2, CYP3A4 | [10,15] |
Clonazepam | CYP3A4, CYP3A5 | [10,29] |
Clopidogrel | CYP2C19 | [30] |
Clozapine | CYP1A2, CYP2D6, CYP3A4, CYP2C19 | [10,31] |
Desipramine | CYP1A2, CYP2D6 | [10,32,33] |
Desvenlafaxine | CYP2C19, CYP3A4 | [15] |
Doxepin | CYP2D6, CYP2C19, CYP2C9 | [10,15,34] |
Duloxetine | CYP1A2, CYP2D6 | [10,15,35] |
Escitalopram | CYP2C19, CYP2D6, CYP3A4 | [10,15,36] |
Fluoxetine | CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 | [10,37] |
Fluvoxamine | CYP2D6, CYP1A2 | [10,15,38] |
Haloperidol | CYP2D6, CYP3A4 | [39] |
Imipramine | CYP2D6, CYP2C19, CYP1A2, CYP3A4 | [10,15] |
Lurasidone | CYP3A4 | [10,15] |
Mirtazapine | CYP1A2, CYP2D6, CYP3A4, CYP2C19 | [10,15,40] |
Nortriptyline | CYP2D6, CYP1A2, CYP2C19, CYP3A4 | [10,33] |
Olanzapine | CYP1A2, CYP2D6 | [10,41] |
Oxcarbazepine | - | [10,42] |
Paroxetine | CYP2D6, CYP3A4 | [10,15] |
Perphenazine | CYP2D6 | [10,43] |
Phenytoin | CYP2C9, CYP2C19 | [44] |
Pimozide | CYP2D6, CYP3A4, CYP1A2 | [10,45] |
Quetiapine | CYP2D6, CYP3A4 | [10,15,46] |
Reboxetine | CYP3A4 | [10,15] |
Risperidone | CYP2D6 | [10,47,48] |
Sertraline | CYP2C19, CYP2B6, CYP2C9, CYP2D6, CYP3A4 | [10,15,49] |
Thioridazine | CYP2D6 | [10,50] |
Trazodone | CYP2D6, CYP3A4, CYP1A2 | [10,51] |
Trimipramine | CYP2C19, CYP2C9, CYP2D6, CYP3A4 | [10,15,52] |
Valproic acid | CYP2A6, CYP2B6, CYP2C9, CYP2C19 | [10,53] |
Venlafaxine | CYP2C19, CYP2D6, CYP3A4 | [10,15,54] |
Vortioxetine | CYP3A4, CYP2C9, CYP2D6, CYP2C19 | [10,15,55] |
Ziprasidone | CYP3A4 | [10,56,57] |
Zolpidem | CYP1A2, CYP2D6, CYP3A4 | [10,58] |
Zonisamide | CYP3A4, CYP2C19 | [59,60] |
Zuclopenthixol | CYP2D6, CYP3A4 | [10,43,61] |
Genes | RS ID | Alleles | SSA AF | AA/AC AF | Eur AF | NE AF | EA AF | CSA AF | Ame AF | Lat AF | Oce AF |
---|---|---|---|---|---|---|---|---|---|---|---|
CYP3A5 | rs55817950, rs776746, rs10264272, rs28383479, rs41303343, rs28365083 | (*1 *2 *3 *6 *7 *8 *9) | 0.54 | 0.50 | 0.71 | 0.62 | 0.49 | 0.78 | 0.83 | 0.75 | 0.74 |
CYP2B6 | rs34223104, rs28399499, rs3211371 | (*1 *5 *7 *16 *18 *22 *34 *35 *36) | 0.44 | 0.52 | 0.64 | 0.52 | 0.66 | 0.61 | n.a. | 0.56 | 0.37 |
CYP2C9 | rs1799853, rs9332131, rs28371685, rs1057910, rs56165452, rs28371686 | (*1 *2 *3 *4 *5 *6 *11 *18 *35 *61) | 86.42 | 86.70 | 80.01 | 76.91 | 96.57 | 78.90 | 88.92 | n.a. | 96.62 |
CYP2C19 | rs12248560, rs28399504, rs41291556, rs72552267, rs17884712, rs4986893, rs6413438, rs4244285, rs72558186, rs56337013 | (*1 *2 *3 *4 *5 *6 *7 *8 *9 *10 *17) | 0.74 | 0.75 | 0.78 | 0.81 | 0.98 | 0.83 | 0.89 | 0.82 | 0.94 |
CYP2D6 | rs1065852, rs5030862, rs28371706, rs5030655, rs5030865, rs3892097, rs35742686, rs5030867, rs28371725, rs59421388, rs1135840, rs16947, rs5030656 | (*1 *2 *3 *4 *5 *6 *7 *8 *9 *10 *11 *12 *14 *17 *19 *20 *21 *28 *29 *30 *31 *32 *34 *35 *36 *37 *39 *40 *41 *42 *45 *46 *47 *49 *51 *52 *54 *55 *56 *57 *58 *59 *64 *65 *69 *70 *72 *73 *82 *83 *84 *85 *87 *88 *91 *94 *95 *98 *99 *100 *101 *102 *103 *104 *105 *109 *111 *114 *115 *117 *119 *121 *123 *125 *126 *128 *129 *132 *133 *135 *136 *138) | ˜1 | ˜1 | ˜1 | ˜1 | ˜1 | ˜1 | ˜1 | ˜1 | 0.85 |
Drug | Related Genes | Indication in the Guidelines | Label Indication | ||
---|---|---|---|---|---|
CPIC | DPWG | FDA | EMA/AIFA | ||
Agomelatine | noRec | noRec | |||
Alprazolam | noRec | noRec | |||
Amitriptyline | CYP2D6 | Y | Y | ||
CYP2C19 | N | Y | |||
Aripiprazole | CYP2D6 | Y | Y | ||
Atomoxetine | CYP2D6 | Y | Y | ||
Bupropion | noRec | noRec | |||
Buspirone | noRec | noRec | NA | ||
Carbamazepine | noRec | noRec | |||
Chlorpromazine | noRec | noRec | |||
Citalopram | CYP2C19 | Y | Y | ||
Clobazam | CYP2C19 | Y | Y | ||
Clomipramine | CYP2D6 | Y | Y | ||
Clonazepam | noRec | noRec | |||
Clopidogrel | CYP2C19 | Y | Y | ||
Clozapine | noRec | noRec | |||
Desipramine | noRec | noRec | NA | ||
Desvenlafaxine | noRec | noRec | NA | ||
Doxepin | CYP2D6 | Y | NA | ||
CYP2C19 | N | NA | |||
Duloxetine | noRec | noRec | |||
Escitalopram | CYP2C19 | Y | Y | ||
Fluoxetine | CYP2D6 | Y | Y | ||
Fluvoxamine | CYP2D6 | Y | N | ||
Haloperidol | CYP2D6 | N | N | ||
Imipramine | CYP2D6 | Y | NA | ||
CYP2C19 | N | NA | |||
Lurasidone | noRec | noRec | |||
Mirtazapine | noRec | noRec | |||
Nortriptyline | CYP2D6 | Y | N | ||
Olanzapine | noRec | noRec | |||
Oxcarbazepine | noRec | noRec | |||
Paroxetine | CYP2D6 | Y | Y | ||
Perphenazine | noRec | noRec | |||
Phenytoin | CYP2C9 | Y | Y | ||
Pimozide | CYP2D6 | N | N | ||
Quetiapine | noRec | noRec | |||
Reboxetine | noRec | noRec | |||
Risperidone | noRec | noRec | |||
Sertraline | CYP2C19 | N | Y | ||
Thioridazine | noRec | noRec | NA | ||
Trazodone | noRec | noRec | |||
Trimipramine | CYP2C19 | Y | Y | ||
Valproic acid | noRec | noRec | |||
Venlafaxine | noRec | noRec | |||
Vortioxetine | noRec | noRec | NA | ||
Ziprasidone | noRec | noRec | |||
Zolpidem | noRec | noRec | |||
Zonisamide | noRec | noRec | |||
Zuclopenthixol | noRec | noRec |
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Zampatti, S.; Fabrizio, C.; Ragazzo, M.; Campoli, G.; Caputo, V.; Strafella, C.; Pellicano, C.; Cascella, R.; Spalletta, G.; Petrosini, L.; et al. Precision Medicine into Clinical Practice: A Web-Based Tool Enables Real-Time Pharmacogenetic Assessment of Tailored Treatments in Psychiatric Disorders. J. Pers. Med. 2021, 11, 851. https://doi.org/10.3390/jpm11090851
Zampatti S, Fabrizio C, Ragazzo M, Campoli G, Caputo V, Strafella C, Pellicano C, Cascella R, Spalletta G, Petrosini L, et al. Precision Medicine into Clinical Practice: A Web-Based Tool Enables Real-Time Pharmacogenetic Assessment of Tailored Treatments in Psychiatric Disorders. Journal of Personalized Medicine. 2021; 11(9):851. https://doi.org/10.3390/jpm11090851
Chicago/Turabian StyleZampatti, Stefania, Carlo Fabrizio, Michele Ragazzo, Giulia Campoli, Valerio Caputo, Claudia Strafella, Clelia Pellicano, Raffaella Cascella, Gianfranco Spalletta, Laura Petrosini, and et al. 2021. "Precision Medicine into Clinical Practice: A Web-Based Tool Enables Real-Time Pharmacogenetic Assessment of Tailored Treatments in Psychiatric Disorders" Journal of Personalized Medicine 11, no. 9: 851. https://doi.org/10.3390/jpm11090851