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COMT

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The COMT gene, residing on chromosome 22, encodes the enzyme catechol-O-methyltransferase, which degrades catecholamines, such as the neurotransmitters dopamine, epinephrine, and norepinephrine. The activity of the COMT enzyme is modulated by genetic variants, one of the best characterized being rs4680 (also known as Val158Met variant or c.322G>A1947A>G). Patients with the COMT rs4680 variant have a decreased likelihood of smoking cessation with nicotine replacement therapy. Tobacco remains the leading preventable cause of death worldwide, yet the efficacy of first-line therapies remains low. Testing COMT may be useful for early identification of patients who may show decreased likelihood of smoking cessation who may benefit from additional support in the form of counseling or alternative medication therapy.

REFERENCES
  1. http://grch37.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=22:19950771-19951771;v=rs4680;vdb=variation;vf=4460
  2. Nicotine chemistry, metabolism, kinetics and biomarkers. Handbook of Experimental Pharmacology. 2009. Benowitz N L, et al.
  3. Association between catechol-O-methyltransferase (COMT) Val/Met genotype and smoking cessation treatment with nicotine: a meta-analysis. Pharmacogenomics. 2015. Choi H D, et al.
  4. COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. Pharmacogenomics Journal. 2013. Herman A I, et al.
  5. Pharmacogenetics of smoking cessation in general practice: results from the patch II and patch in practice trials. Nicotine & Tobacco Research. 2011. David S P, et al.

CYP1A2

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Located on the plus strand of chromosome 15, CYP1A2 encodes the Cytochrome P450 family 1 subfamily A type A2 enzyme, which mediates liver metabolism of 9% of clinically important drugs (e.g., clozapine, olanzapine), procarcinogens (e.g., benzopyrene and aflatoxin b1), and endogenous substrates (e.g., steroids and arachidonic acid). For many drugs, CYP1A2 is not the sole metabolizing enzyme nor is it active at the rate-limiting step. The genetic component of variation in CYP1A2 activity is estimated at up to 75%, with environmental factors making up the remaining difference such as smoking (induction) and oral contraceptive use in women (inhibition). A recent pathway-based analysis in human liver samples estimated that genetic variants and non-genetic factors may account for 42%, 38%, and 33% of the variation of CYP1A2 at the catalytic activity, protein expression, and mRNA levels, respectively. CYP1A2 is important for dosing of several antipsychotics and for both drug efficacy and adverse drug reactions. CYP1A2 is the main CYP isoform involved in clozapine metabolism; case studies have shown that in ultrarapid metabolizers of clozapine who presented as resistant to treatment, improved patient outcomes were obtained by increased clozapine doses and co-administration with the CYP1A2 inhibitor fluvoxamine. For concomitant use of CYP1A2 inhibitors or inducers, the US Food and Drug Administration recommends clozapine dosage adjustments, monitoring for adverse reactions or lack of efficacy, or discontinuation of co-medication. Genotyping CYP1A2 may be useful in identifying patient phenotypes to assist drug therapy decision-making.

References
  1. Clozapine FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenetics and Genomics. 2012. Thorn C F, et al.
  3. Pathway-Targeted Pharmacogenomics of CYP1A2 in Human Liver. Frontiers in Pharmacogenomics. 2010. Klein K, et al.
  4. Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. Journal of Clinical Psychopharmacology. 2004. Eap C B, et al.
  5. Metabolism of clozapine by cDNA-expressed human cytochrome p450 enzymes. Drug Metabolism and Disposition. 1997. Linnet K and Olesen O V.
  6. CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations. Therapeutic Drug Monitoring. 2015. Czerwensky F, Leucht S, Steimer W.
  7. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics Journal. 2009. Laika B, et al.
  8. Cigarette smoking has a differential effect on the plasma level of clozapine in Taiwanese schizophrenic patients associated with the CYP1A2 gene −163A/C single nucleotide polymorphism. Psychiatric Genetics. 2016. Huang H C, et al.

CYP2B6

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Located on the plus strand of chromosome 19, CYP2B6 encodes the Cytochrome P450 family 2, subfamily B type 6 enzyme, which mediates liver and brain metabolism of 4% of the top 200 prescribed medications. CYP2B6 is highly inducible by several drugs and other xenobiotics. Variation in CYP2B6 expression varies over a 20-250-fold range, due to differences in transcriptional regulation and genetic variations. CYP2B6 is the primary enzyme involved in the metabolism of efavirenz and nevirapine, which have a narrow therapeutic window. Variants in CYP2B6 have been associated with efficacy and tolerability of adverse effects in efavirenz, cyclophosphamide, and bupropion, among others. Genotyping CYP2B6 can aid efavirenz dosing and may decrease the cost of HIV treatment.

References
  1. Efavirenz FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Dose optimization of efavirenz based on individual CYP2B6 polymorphisms in Chinese patients positive for HIV. CPT Pharmacometrics Systems & Pharmacology. 2016. Hui K H, et al.
  3. Cost-effectiveness of CYP2B6 genotyping to optimize efavirenz dosing in HIV clinical practice. Pharmacogenomics. 2015. Schackman B R, et al.

CYP2C9

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Located on the plus strand of chromosome 10, CYP2C9 encodes the Cytochrome P450 family 2 subfamily C type 9 enzyme, which is primarily expressed in the liver and mediates metabolic clearance of 15%-20% of all drugs undergoing Phase I metabolism. The gene coding for the CYP2C9 enzyme is highly polymorphic, including functional variants of major pharmacogenetic importance. Changes in metabolic activity caused by genetic variants in CYP2C9 play a major role in pathogenesis due to ADRs. Patients with low enzyme activity are at risk of adverse drug reactions (ADRs), especially for CYP2C9 substrates with a narrow therapeutic window, such as S-warfarin, phenytoin, glipizide, and tolbutamide. Professional guidelines exist for the use of CYP2C9 genotyping in guiding prescription of several medications, including warfarin, phenytoin, and celecoxib. For example, in patients who are known or suspected CYP2C9 poor metabolizers for celecoxib, the US Food and Drug Administration recommends caution when administering celecoxib with a dosage reduction by 50% or use of alternative therapy for juvenile rheumatoid arthritis. Genotyping CYP2C9 can aid with the selection and dosing of these medications and may prevent ADRs.

References
  1. Celecoxib FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics‐guided warfarin dosing: 2017 update. Clinical Pharmacology & Therapeutics. 2017. Johnson J, et al.
  3. Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. Journal of Pharmacology and Experimental Therapeutics. 2000. Tang C, et al.
  4. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA‐B genotypes and phenytoin dosing. Clinical Pharmacology & Therapeutics. 2014. Caudle K E, et al.

CYP2C19

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CYP2C19, located on the plus strand of chromosome 10, encodes the Cytochrome P450 family 2 subfamily C type 19 enzyme, which mediates liver (and small intestinal) metabolic oxidation of 10-15% of clinically relevant drugs and drug classes, including antidepressants, benzodiazepines, mephenytoin, proton pump inhibitors, and the antiplatelet prodrug clopidogrel. Variants in the gene include loss-of-function alleles (e.g., *2, *3) and a promoter variant that causes increased gene expression (e.g., *17). CYP2C19 is the primary enzyme involved in the metabolism of clopidogrel, therefore genotyping for CYP2C19 may predict patient antiplatelet response to the drug. In addition, CYP2C19 genotyping is useful for dosing various antidepressants including tricyclic antidepressants (together with CYP2D6) and SSRIs, proton-pump inhibitors (PPIs) such as omeprazole, and the antifungal voriconazole. Professional guidelines exist for the use of CYP2C19 genotyping for guiding prescriptions of these medications. Specifically, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for clopidogrel treatment, indicating that poor or intermediate CYP2C19 metabolizers should use an alternative antiplatelet therapy (e.g., prasugrel, ticagrelor), and ultrarapid CYP2C19 metabolizers should follow label recommended dosage and administration even though at least one *17 allele may be associated with increased risk of bleeding. Genotyping CYP2C19 can aid clopidogrel dosing and lessen the risk of bleeding, decrease the risk of ADRs with antidepressants, and help achieve efficacy with PPIs and voriconazole.

References

  1. Clopidogrel FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clinical Pharmacology and Therapeutics. 2013. Scott S A, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.
  4. Omeprazole therapy and CYP2C19 genotype. Medical Genetics Summaries. Dean L. Available at: https://www.ncbi.nlm.nih.gov/books/NBK100895/.
  5. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2C19 and voriconazole therapy. Clinical Pharmacology and Therapeutics. 2016. Moriyama B, et al.
  6. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology and Therapeutics. 2017. Hicks, et al.
  7. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology and Therapeutics. 2015. Hicks et al.

CYP2D6

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CYP2D6, located on the minus strand of chromosome 22, encodes the Cytochrome P450 family 2 subfamily D type 6 enzyme, which mediates hepatic first-pass metabolic oxidation of numerous drugs, including the anti-arrhythmics, antidepressants, antipsychotics, beta blockers-adrenergic blocking agents, antiemetics, analgesics, and antitussives. Variants in this gene may reduce or abolish enzyme function; variations in copy number also exist, which may lead to increased function or complete deletion of the gene, resulting in phenotypes ranging from no to increased function compared to normal. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for codeine, desipramine, fluvoxamine, nortriptyline, ondansetron, paroxetine, and tropisetron treatment based on CYP2D6 metabolizer status. For example in codeine guidelines, CPIC recommends use of alternative analgesics for CYP2D6 poor metabolizers based on lack of efficacy and for ultrarapid metabolizers based of potential for toxicity. CPIC recommends use of label age- or weight-specific dosing in normal and intermediate metabolizers with an additional recommendation for intermediate metabolizers to consider alternative analgesics such as morphine or a non-opioid if there is no response. In addition, CYP2D6 genotyping may help in predicting outcomes with tamoxifen chemotherapy in breast cancer. Genotyping CYP2D6 can aid opioid treatment, antidepressant therapy, tamoxifen dosage and response, and it can prevent toxicity-related ADRs with all of these medications.

References
  1. Codeine FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for cytochrome P450 2D6 (CYP2D6) genotype and codeine therapy: 2014 update. Clinical Pharmacology and Therapeutics. 2014. Crews K R, et al.
  3. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology and Therapeutics. 2017. Hicks, et al.
  4. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology and Therapeutics. 2015. Hicks, et al.
  5. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

CYP3A4

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Cytochrome P450 family 3 subfamily A type 4 enzyme (CYP3A4) is encoded by the CYP3A4 gene located on the minus strand of chromosome 7. Along with CYP3A5, CYP3A4 is the predominant cytochrome P450 enzyme expressed in the adult human liver and is involved in the metabolism of about 50% of all drugs. CYP3A4 activity predominates in Caucasians, and CYP3A5 predominates in individuals of African descent; these enzymes have overlapping substrate specificities. Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated in the treatment of elevated cholesterol and prevention of cardiovascular events. CYP3A4 is the primary enzyme involved in the metabolism of simvastatin; therefore it may help in predicting patient response to the medication. The US Food and Drug Administration warns of risk of myopathy and rhabdomyolysis which is increased by high plasma levels of simvastatin. The FDA recommends that using simvastatin concomitantly with CYP3A4 inhibitors (such as antifungal azoles like itraconazole and ketoconazole, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, or large quantities of grapefruit juice) should be avoided. Genotyping CYP3A4 can be useful in identifying patient phenotypes to aid in statin therapy decision-making.

References
  1. Simvastatin FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Individual and combined associations of genetic variants in CYP3A4, CYP3A5, and SLCO1B1 with simvastatin and simvastatin acid plasma concentrations. Journal of Cardiovascular Pharmacology. 2015. Luzum J A, et al.
  3. CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort. Pharmacogenetics and Genomics. 2014. Kitzmiller J P, et al.

CYP3A5

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Cytochrome P450 family 3 subfamily A type 5 (CYP3A5) is encoded by the CYP3A5 gene, located on the minus strand of chromosome 7. Along with CYP3A4, CYP3A5 is the predominant cytochrome P450 enzyme expressed in the adult human liver. CYP3A4 activity predominates in Caucasians, and CYP3A5 predominates in individuals of African descent; these enzymes have overlapping substrate specificities. Most drugs metabolized by CYP3A4 are also metabolized by CYP3A5, with a few exceptions. For example, tacrolimus is a calceineurin inhibitor immunosuppressant used in transplant recipients and is predominantly affected by CYP3A5 genotype. Tacrolimus has a low therapeutic index with a wide range of side effects and large inter-individual variability in its pharmacokinetics. In particular, the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for tacrolimus, indicating that increasing the starting dose by 1.5 to 2 times the recommended starting dose in patients who are CYP3A5 intermediate or normal metabolizers, though total starting dose should not exceed 0.3 mg/kg/day. CPIC recommends poor CYP3A5 metabolizers initiate therapy with the standard recommended dose. Genotyping CYP3A5 may be useful in identifying patient phenotypes to assist drug therapy decision-making.

References
  1. Tacrolimus FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clinical Pharmacology and Therapeutics. 2015. Birdwell K A, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

DPYD

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The DPYD gene, located on the minus strand of chromosome 1, encodes the enzyme dihydropyrimidine dehydrogenase (DPD). This enzyme is involved in the degradation pathway of fluoropyrimidines, such as 5-fluorouracil, capecitabine, and tegafur. Decreased activity of DPD can lead to severe or fatal toxicity in normal dosing of fluoropyrimidines. The activity of DPD is modulated by multiple variants, including *1, *4, *5, *6, *9A (normal activity) and *2A, *13 and rs67376798 T>A (no activity). The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for fluoropyrimidine treatment, indicating patients who are homozygous for DPYD non-functional variants, *2A (rs3918290), *13 (rs55886062), and rs67376798 A (on the positive chromosomal strand), should use an alternative drug. CPIC indicates that heterozygous patients (intermediate activity) should consider a 50% reduction in starting dose. Genotyping DPYD may be useful in identifying patients at increased risk for toxicity when considering fluoropyrimidine treatment.

References

  1. Fluorouracil FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clinical Pharmacology and Therapeutics. 2013. Caudle K E, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

DRD2

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The DRD2 gene, residing on the minus strand of chromosome 11, encodes dopamine receptor D2. Dopamine receptor D2 is a G protein-coupled receptor highly expressed in the pituitary gland and central nervous system. This receptor is targeted by many antiparkinsonian agents (acting as agonists) as well as typical and atypical antipsychotics (acting as antagonists). Variants in this gene have been associated with efficacy and toxicity of antipsychotics. In particular, rs1799978 A>G is a promoter variation that influences the transcript expression. Evidence shows that this variant is related to likelihood of response to risperidone in patients with schizophrenia. However, the response to risperidone is influenced by many other clinical and genetic factors. Genotyping DRD2 may be useful in determining possible causes for poor response to risperidone.

References
  1. Risperidone FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics. 2008. Ikeda M, et al.
  3. The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. International Journal of Neuropsychopharmacology. 2007. Xing Q, et al.

F2

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The F2 gene, residing on chromosome 11, encodes prothrombin (coagulation factor II), which is cleaved to form the serine protease thrombin during blood clotting. Mutations in the 3’ untranslated region of this gene (AA or GA genotype) are associated with increased risk of deep vein thrombosis for women taking hormonal contraceptives (ethinyl estradiol/norelgestromin) as compared to women with the GG genotype who are not taking oral contraceptives. Genotyping F2 may be useful in identifying patients at increased risk of thrombosis due to prothrombin thrombophilia.

References
  1. Ethinyl estradiol FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors. Journal of Thrombosis and Haemostatsis. 2015. Bruzelius M, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

F5

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The F5 gene, residing on the minus strand of chromosome 1, encodes the coagulation cofactor Factor 5. Mutations in this gene are associated with increased risk of venous thromboembolism for women taking hormonal contraceptives as compared to women with the GG genotype who are not taking oral contraceptives. The putative mechanism for this outcome is that the mutation enhances the induction of activated protein C resistance by oral contraceptives and hormonal replacement therapy, which can lead to hypercoagulation. The Royal Dutch Pharmacists Association (DPWG) released guidelines for hormonal contraceptives treatment, indicating that estrogen-containing oral contraceptives should be avoided and alternative forms of contraception used in individuals who carry the F5 allele and have a family history of thrombotic events. Genotyping F5 may be useful in identifying patients at increased risk of thrombosis due to Factor V Leiden thrombophilia.

References
  1. Ethinyl estradiol FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors. Journal of Thrombosis and Haemostatsis. 2015. Bruzelius M, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

GRIK4

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The GRIK4 gene, residing on chromosome 11, encodes the glutamate receptor, ionotropic, kainate 4. It is involved in glutamate neurotransmission, with glutamate being the main neurotransmitter in the human brain. Response to the SSRI citalopram, as well as other antidepressants, can be predicted based on a variant in this gene. Response to citalopram depends on multiple genetic and clinical factors (including HTR2A), therefore a treatment decision should not be made based on GRIK4 alone. Genotyping GRIK4 may be useful in determining possible causes for poor response to citalopram.

REFERENCES
  1. GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. Pharmacogenomics. 2014. Kawaguchi D M, et al.
  2. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology 2010. Horstmann S, et al.
  3. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry. 2010. Kato M, et al.
  4. Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatric Services (Washington D.C.). 2009. Laje G, et al.
  5. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. The American Journal of Psychiatry. 2007. Paddock S, et al.

HTR2A

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The HTR2A gene, residing on chromosome 13, encodes the 5-hydroxytryptamine (serotonin) receptor 2A. This metabotropic receptor mediates the response of many antidepressant and antipsychotic drugs (especially second generation) and is found to be downregulated as a pharmacodynamics effect of chronic administration of selective serotonin reuptake inhibitors (SSRIs) and first generation antipsychotics. Patient response to many of these drugs may be predicted by variants in this gene, in particular rs7997012 A>G. Response to citalopram depends on multiple genetic and clinical factors, therefore a treatment decision should not be made based on HTR2A alone. However, genotyping HTR2A may be useful in determining possible causes for poor response to citalopram.

References
  1. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010. Horstmann S, et al.
  2. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry. 2010. Kato M, et al.
  3. Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatric Services (Washington D.C.). 2009. Laje G, et al.

HTR2C

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The HTR2C gene, residing on the X chromosome, encodes the 5-hydroxytryptamine (serotonin) receptor 2C. Many antipsychotics and antidepressants target this metabotropic receptor as either agonists or antagonists, leading to downregulation in both cases. This receptor and schizophrenia has been associated with weight gain in patients treated with olanzapine. Variants in HTR2C are associated with a protective effect from weight gain while taking olanzapine. Genotyping HTR2C may be useful in identifying patients on olanzapine with reduced risk of weight gain.

References
  1. Olanzapine FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. International Journal of Psychiatry in Clinical Practice. 2014. Ma X, et al.
  3. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics Journal. 2010. Laika B, et al.

IFNL4

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The IFNL4 gene, residing on the minus strand of chromosome 19, encodes interferon, lambda 4, and was recently identified as important to the immune response to hepatitis C. The IFNL4 gene encodes for the functional protein interferon, lambda 4 in most people from African origin; in about half of people from European origin and most of people from Asian origin, IFNL4 exhibits a variant that renders the gene non functional. Another variant in this gene, rs12979860 C>T, is associated with deviation of sustained virologic response (SVR) rates. The hypothesis is the rs12979860 C>T variant improves innate immune response and increased viral kinetics. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for pegylated-interferon alpha containing regimens, indicating that this variant is the strongest baseline predictor of response to peginterferon alpha containing regimens in HCV genotype 1 patients. CPIC guidelines state patients with the favorable response genotype (rs12979860 CC) have increased likelihood of response (higher SVR rate) to peginterferon alpha containing regimens as compared to patients with unfavorable response genotype (rs12979860 CT or TT). These guidelines are also reflected in the FDA label for peginterferon alpha-based regimens. Genotyping the rs12979860 C>T variant may be useful in predicting responsiveness to peginterferon alpha containing regimens in patients with hepatitis C viral infections. Until recently, rs12979860 C>T was thought to be located in a regulatory region upstream of IFNL3 (also referred to as IL28B). Therefore, current CPIC guidelines and the FDA label refer to these genes as IL28B and IFNL3.

REFERENCES
  1. Peginterferon alfa-2a FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and peginterferon alpha based regimens. Clinical Pharmacology and Therapeutics. 2013. Muir A J, et al.
  3. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature Genetics. 2013. Prokunina-Olsson L, et al.
  4. Loss of function of the new interferon IFN-λ4 may confer protection from hepatitis C. Nature Genetics. 2013. Booth D & George J.
  5. IFN-λ4: The paradoxical new member of the interferon lambda family. Journal of Interferon & Cytokine Research. 2014. O’Brien T R, et al.

NUDT15

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The NUDT15 gene, residing on the plus strand of chromosome 13, encodes nucleotide diphosphate linked moiety X (nudix)-type hydrolase motif 15. This type of protein catalyzes the hydrolysis of nucleoside diphosphates that are oxidized bases that can result in base mispairing during nucleic acid synthesis, and thereby cause translational errors. NUDT15 also inactivates thiopurine (e.g., azathioprine, mercaptopurine, and thioguanine) metabolites. Patients carrying variants in this gene may be at higher risk of developing leukopenia or alopecia as a result of thiopurine treatment for inflammatory bowel diseases or acute lymphoblastic leukemia compared to patients without these variants. Functionally, rs116855232 C>T has been associated with impaired NUDT15 activity. Genotyping NUDT15 is useful in predicting potential for toxicity to thiopurine drugs.

References
  1. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature Genetics. 2016. Moriyama T, et al.
  2. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. 2015. Yang J, et al.
  3. NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn’s disease. Alimentary Pharmacology & Therapeutics. 2016. Zhu, et al.
  4. NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children’s Cancer Center of Lebanon. Pediatric Blood Cancer. 2017. Zgheib N, et al.
  5. TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. British Journal of Haematology. 2017. Soler A, et al.

OPRM1

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The OPRM1 gene, residing on chromosome 6, encodes the mu-1 opioid receptor, a G protein-coupled receptor highly expressed in the spinal cord and other areas of the central nervous system, which is the primary site of action of opioids like morphine, alfentanil, tramadol, fentanyl, and methadone. Variants in this gene have been linked to differential efficacy of opioids for pain. The rs1799971 A>G variant has been linked to response to certain medications, in particular alfentanil, codeine, and tramadol. This variant codes for different isoforms of the protein, and the impact on the function of the OPRM1 receptor is unclear, potentially modulating affinities to endogenous endorphins. Although OPRM1 likely plays a role in the clinical response of opioids, evidence is contradictory for many of these medications, as effects of pain medication involve multiple genes that contribute to the global response. For OPRM1 specifically, clinical data is consistent on alfentanil, codeine, and tramadol. Evidence shows the pharmacokinetics of various opioids is the main modulator of response to treatment. Genotyping OPRM1 may be useful in predicting response to various opioids.

References
  1. Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic-pharmacodynamic study. British Journal of Anaesthesia. 2009. Ginosar Y, et al.
  2. The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenetics and Genomics. 2006. Oertel B G, et al.
  3. Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia. Minerva Anestesiologica. 2011. Zhang W, et al.
  4. The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics Journal. 2015. Baber M, et al.
  5. Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clinical Pharmacology & Therapeutics. 2012. Sistonen J, et al.

SLC6A4

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The SLC6A4 gene, residing on chromosome 17, encodes the serotonin transporter (SERT), or 5HTT, which is the site of action for selective serotonin reuptake inhibitors (SSRIs). A 44 base pair insertion in the promoter region of SLC6A4 gives rise to two variants: the “L” or long variant and the “S” or short variant. The L variant is associated with increased transcriptional efficacy of the serotonin transporter and is also linked to the rs25531 T>C variant, which further modulates transcription. The minor allele substitution A>G is almost always in phase with the L allele and reduces the transcriptional efficacy comparable to that of S allele. The S/S genotype has been associated with reduced likelihood and potentially slower response to the SSRIs fluoxetine and fluvoxamine and possibly citalopram and escitalopram. The opposite trend in response has been observed in East Asian populations, showing increased likelihood and potentially quicker response in carriers of the S allele. The S/S genotype is more frequent in the East Asian population, compared to the Caucasian and African American population. In combination with other genetic findings and clinical factors, SLC6A4 genotype may be useful in understanding patient response to SSRIs.

References
  1. Population frequencies of the triallelic 5HTTLPR in six ethnically diverse samples from North America, Southeast Asia, and Africa. Behavior Genetics. 2015. Haberstick B, et al.
  2. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. European Neuropsychopharmacology. 2012. Porcelli S, et al.
  3. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Molecular Psychiatry. 2006. Serretti A, et al.
  4. The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients. Psychiatric Genetics. 2008. Smits K, et al.

SLCO1B1

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Located on the plus strand of chromosome 19, SLCO1B1 encodes the OATP1B1 transporter, which mediates the transport of statins from the blood into the liver. SLCO1B1 variants affect the transporter function, which can affect the efficacy and tolerability of statin medications. Clinically, rs4149056 T>C (characterizing *5, *15 and *17) has been associated with reduced SLCO1B1 function and increased risk for simvastatin-induced myopathy. In other words, the presence of at least one *5, *15 or *17 allele yield the same phenotype and clinical recommendation with respect to the risk of myopathy. Recent research indicates that rs4149056 T>C may also be associated, and potentially higher rosuvastatin, atorvastatin, and fluvastatin levels with unknown effect on their efficacy. In addition, the rs4149015 G>A SNP (characterizing 17 and 21) has also been associated with higher area under the curve (AUC) and reduced efficacy of pravastatin, which demonstrate an effect of rs4149015 G>A on SLCO1B1 function in vivo. The effect of rs4149015 G>A on simvastatin remains unclear. To the best of our knowledge, no study reports data on this location independently from the rs4149056 T>C variant (i.e., effects of rs4149015 G>A have likely been studied in a *17 background). A recent publication suggests that rs4149015 G>A may affect the pharmacokinetics of simvastatin in a Chinese cohort. Therefore, an impact of rs4149015 G>A on simvastatin cannot be excluded, but the increased risk of myopathy remains to be demonstrated. Recently, studies also demonstrated an impact of rs4149056 T>C on methotrexate toxicity in patients with acute lymphoblastic leukemia (ALL), where methotrexate is typically used at high dose. For simvastatin, the US Food and Drug Administration recommends against 80mg daily dosage in patients with the C allele at SLCO1B1 rs4149056, as there are modest increases in myopathy risk even at lower simvastatin doses (40mg daily); if optimal efficacy is not achieved with a lower dose, the FDA recommends alternate agents should be considered. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for simvastatin, indicating recommended dosing based on SLCO1B1 phenotype. Genotyping SLCO1B1 may be useful for predicting statin-associated myopathy for various statins.

References
  1. Simvastatin FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clinical Pharmacology and Therapeutics. 2014. Ramsey L B, et al.
  3. Clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clinical Pharmacology and Therapeutics. 2012. Wilke R A, et al.
  4. Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenetics and Genomics. 2005. Niemi M, et al.
  5. Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood. 2013. Radtke S, et al.
  6. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics Journal. 2012. Brunham L R, et al.
  7. SLCO1B1 variants and statin-induced myopathy—a genomewide study. New England Journal of Medicine. 2008. Link E, et al. (this is the SEARCH collab)
  8. Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort. Pharmacogenetics and Genomics. 2015. Meyer zu Schwabedissen H E, et al.
  9. Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid. Pharmacogenetics and Genomics. 2015. Choi H Y, et al.
  10. The ROCK/GGTase Pathway Are Essential to the Proliferation and Differentiation of Neural Stem Cells Mediated by Simvastatin. Journal of Molecular Neuroscience. 2016. Zhang C, et al.
  11. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. Journal of Clinical Oncology. 2009 Treviño L R, et al.

TPMT

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The TPMT gene, residing on the minus strand of chromosome 6, encodes the thiopurine S-methyltransferase enzyme that catalyzes S-methylation of heterocyclic sulfhydryl compounds such as azathioprine, mercaptopurine, and thioguanine. The methylation of these drugs is the inactivation pathway, so decreased activity of this enzyme leads to toxicity due to overexposure to active drug. The 3A allele is comprised of the two SNPs rs1800460 and rs1142345, which are in high linkage disequilibrium, though may occur as individual mutations, denoted as 3B and 3C respectively. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for thioguanine based on TPMT genotype, which recommend initiating therapy with reduced doses and continual adjustment of doses based on the degree of myelosuppression and disease-specific guidelines. Reduced doses of thioguanine are recommended for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles. CPIC also recommends considering alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles. Genotyping TPMT may be useful in predicting potential for toxicity to thiopurine drugs.

References
  1. Thioguanine FDA Drug Label; mercaptopurine FDA label; azathioprine FDA label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation. Pharmacogenetics and Genomics. 2013. Liang J J, et al.
  3. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clinical Pharmacology and Therapeutics. 2013. Relling M V, et al.
  4. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

UGT1A1

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The UGT1A1 gene, located on chromosome 2, belongs to the family of UDP-glucuronosyltransferases, which mediate glucuronidation of target substrates. Glucuronidation renders the substrates water soluble, thus making them available for biliary or renal elimination. UGT1A1 is expressed in the liver, colon, intestine, and stomach. In the liver, it is the sole enzyme responsible for the metabolism of bilirubin, the hydrophobic breakdown product of heme catabolism. UGT1A1 also is involved in the metabolism of irinotecan, nilotinib, pazopanib, atazanavir, and belinostat, and genetic variation in UGT1A1 indicates risk for adverse effects (neutropenia, hyperbilirubinemia and other toxicities) for these drugs. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir that recommend considering advising individuals who carry two decreased function UGT1A1 alleles about a substantial likelihood of developing jaundice, which may cause non-adherence. The CPIC dosing guideline recommends that alternative agents be considered if the risk of non-adherence due to jaundice is high. The risk of jaundice-related discontinuation is low and very low for individuals carrying one or no decreased function UGT1A1 alleles. For irinotecan, nilotinib, pazopanib, and belinostat, increased risk of toxicities are reported and warnings exist in the FDA labels of these medications. Genotyping UGT1A1 may be useful for identifying patients at increased risk of adverse drug reactions with these medications used in oncology and infectious disease.

References
  1. Atazanavir, belinostat, irinotecan, nilotinib and pazopanib FDA Drug Labels. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. Clinical pharmacogenetics implementation consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clinical Pharmacology and Therapeutics. 2015. Gammal R S, et al.
  3. Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.

VKORC1

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The VKORC1 gene, residing on the minus strand of chromosome 16, encodes Vitamin K epoxide reductase, which is a key enzyme in the Vitamin K cycle. VKORC1 mediates conversion of Vitamin K-epoxide to Vitamin K, which is the rate-limiting step in physiological Vitamin K recycling. The availability of reduced Vitamin K is of particular importance for several coagulation factor proteins that require it as a cofactor. It is of therapeutic interest for its contribution to inter-individual variation in warfarin anticoagulant dose requirements. A single variant in VKORC1 promoter, rs992323 G>A is largely responsible for the variation in individual warfarin daily dose requirements. Individuals with GG genotypes require higher (or normal) warfarin daily maintenance doses, while individuals with variants in VKORC1, including heterozygote GA and homozygote AA genotypes, require lower warfarin daily maintenance doses. However, the overall warfarin daily maintenance dose depends on age, gender, height, weight, diet, genotypes of CYP2C9 and VKORC1, and other known/unknown genetic and environmental factors. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for warfarin, indicating recommendations for dosing for adult and pediatric patients specific to continental ancestry, and is based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823. Genotyping VKORC1 may be useful for identifying patients who may require warfarin dosing adjustments.

References
  1. Warfarin FDA Drug Label. US Food Drug Adm. 2016. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
  2. WarfarinDosing.org
  3. Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clinical Pharmacology and Therapeutics. 2017. Johnson J A, et al.