Pharmacogenomics of CYP2C9: Functional and Clinical Considerations †
Abstract
:1. Introduction
2. CYP2C9 Substrate Selectivity
3. CYP2C9 Structure–Function
4. Clinical Relevance of CYP2C9
4.1. Clinically Relevant Substrates
4.2. CYP2C9 Inducers and Inhibitors
5. CYP2C9 Genetic Polymorphisms
5.1. Background
5.2. Missense and Frameshift Variants in CYP2C9
5.3. Functional Significance of CYP2C9 Missense Variants
5.4. Variants in Non-Coding Regions
5.5. Linkage Disequilibrium with Other CYP2C Genes
6. Clinical Significance of CYP2C9 Polymorphisms
6.1. Coumarin Anticoagulants
6.2. Sulfonylureas
6.3. Nonsteroidal Antiinflammatory Drugs
6.4. Phenytoin
6.5. Miscellaneous
7. Warfarin Dosing Algorithms
8. Contemporary Translational Efforts
8.1. Pre-Emptive Genotyping
8.2. The Problem of Variants of Uncertain Significance
9. Future Prospects
9.1. Computational Approaches
9.2. Large-Scale Functional Assays
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Drug Class | Drugs |
---|---|
Anticoagulants | Acenocoumarol, phenprocoumon, S-warfarin |
Antihypertensives | Irbesartan, losartan |
NSAIDs | Celecoxib, diclofenac, etodolac, ibuprofen, indomethacin, lornoxicam, mefenamic acid, suprofen, tenoxicam |
Oral hypoglycemic agents | Chlorpropamide, glibenclamide, gliclazide, glimepiride, nateglinide, tolbutamide |
Miscellaneous | Bosentan, fluvastatin, mestranol, phenytoin, torsemide |
SNP | Effect | *Allele | Sequence Change Europeans | Overall Frequency Worldwide | European Frequency | African Frequency | East Asian Frequency | South Asian Frequency | Effect |
---|---|---|---|---|---|---|---|---|---|
rs1799853 | p.Arg144Cys | *2 | c.430C>T | 0.0914 | 0.1268 | 0.0235 | 0.0003 | 0.046 | PolyPhen: probably damaging; SIFT:tolerated; other:impaired S-warfarin metabolism in vitro [77] and decreased dose in vivo [82] |
rs1057910 | p.Ile359Leu | *3 | c.1075A>C | 0.0637 | 0.0688 | 0.0126 | 0.0338 | 0.1131 | PolyPhen: possibly damaging; SIFT: deleterious; other: impaired S-warfarin and tolbutamide metabolism in vitro [78,79] and decreased warfarin dose in vivo [82] |
rs2256871 | p.His251Arg | *9 | c.752A>G | 0.0067 | 0.0002 | 0.0754 | 0.0001 | 0.0001 | PolyPhen: probably damaging; SIFT: deleterious; other: no effect on phenytoin clearance in vivo [90] |
rs7900194 | p.Arg150His | *8 | c.449G>A | 0.0052 | 0.0003 | 0.056 | 0.0001 | 0.0006 | PolyPhen:benign; SIFT:tolerated; other: increased activity towards tolbutamide in vitro [91], decreased activity towards phenytoin in vivo [90], decreased warfarin activity in vitro and in vivo [92] |
rs28371685 | p.Arg335Trp | *11 | c.1003C>T | 0.0038 | 0.0021 | 0.0214 | 0.0001 | 0.0019 | PolyPhen: probably damaging; SIFT: deleterious; other: decreased activity towards warfarin in vivo and in vitro [87,91] |
rs72558189 | p.Arg125His | *14 | c.374G>A | 0.003 | 0.0001 | >0.0001 | 0.0001 | 0.0204 | PolyPhen:benign; SIFT:deleterious; other: very low activity in vitro towards tolbutamide and warfarin [93] |
rs9332239 | p.Pro489Ser | *12 | c.1465C>T | 0.0019 | 0.003 | 0.0006 | 0 | 0.0002 | PolyPhen: possibly damaging; SIFT: deleterious; other: decreased warfarin dose requirement [88] |
rs2837168 | p.Asp360Glu | *5 | c.1080C>G | 0.0012 | <0.0001 | 0.0127 | 0 | 0 | PolyPhen: probably damaging; SIFT: deleterious; other: decreased activity towards warfarin and diclofenac in vitro [94]; decreased phenytoin clearance in vivo [90] |
rs9332131 | p.Lys273Arg (fsTer34) | *6 | c.818delA | 0.0009 | <0.0001 | 0.0105 | 0 | 0 | Frameshift so inactivating; other: impaired phenytoin clearance in vivo [95] |
rs182132442 | p.Pro279Thr | *29 | c.835C>A | 0.0004 | 0.0005 * | 0 | 0.0016 | 0.0001 | PolyPhen:benign; SIFT:tolerated; other: decreased activity in vitro with tolbutamide [89]; decreased warfarin clearance in vitro [93] |
rs72558192 | p.Thr299Ala | *52 | c.895A>G | 0.0002 | 0 | 0 | 0.0035 | 0 | PolyPhen: probably damaging; SIFT: deleterious; other: mutation of known active residue based on crystal structures of flurbiprofen- and warfarin-bound CYP2C9 [96], decreased activity in vitro with tolbutamide [97] |
rs72558187 | p.Leu90Pro | *13 | c.269T>C | 0.0001 | 0 | 0 | 0.002 | 0 | PolyPhen:benign; SIFT:tolerated; other: decreased activity in vitro with tolbutamide [97] |
rs7900194 | p.Arg150Leu | *27 | c.449G>T | 0.0001 | 0 | 0 | 0.0017 | >0.0001 | PolyPhen:benign; SIFT:tolerated; other: decreased activity in vitro with tolbutamide [97]; decreased warfarin clearance in vitro [93] |
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Daly, A.K.; Rettie, A.E.; Fowler, D.M.; Miners, J.O. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J. Pers. Med. 2018, 8, 1. https://doi.org/10.3390/jpm8010001
Daly AK, Rettie AE, Fowler DM, Miners JO. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. Journal of Personalized Medicine. 2018; 8(1):1. https://doi.org/10.3390/jpm8010001
Chicago/Turabian StyleDaly, Ann K., Allan E. Rettie, Douglas M. Fowler, and John O. Miners. 2018. "Pharmacogenomics of CYP2C9: Functional and Clinical Considerations" Journal of Personalized Medicine 8, no. 1: 1. https://doi.org/10.3390/jpm8010001
APA StyleDaly, A. K., Rettie, A. E., Fowler, D. M., & Miners, J. O. (2018). Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. Journal of Personalized Medicine, 8(1), 1. https://doi.org/10.3390/jpm8010001