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1.

Desipramine response

MedGen UID:
851737
Concept ID:
CN233052
Sign or Symptom
2.

Selective serotonin reuptake inhibitor (SSRI) response

MedGen UID:
808078
Concept ID:
CN221268
Sign or Symptom
3.

Trimipramine response

MedGen UID:
808073
Concept ID:
CN221259
Sign or Symptom
4.

Fluvoxamine response

Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of major depressive and anxiety disorders, and may be used to treat other psychiatric conditions. Fluvoxamine is metabolized by cytochrome P450 2D6 (CYP2D6) and variations in CYP2D6 may affect drug exposure. CYP2D6 poor metabolizers showed greater drug exposure to fluvoxamine compared to extensive metabolizers at similar drug doses while data are lacking describing the effect of CYP2D6 ultrarapid metabolism on fluvoxamine therapy. Therapeutic guidelines for the SSRI fluvoxamine based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

MedGen UID:
808068
Concept ID:
CN221254
Sign or Symptom
5.

Paroxetine response

Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of major depressive and anxiety disorders, and may be used to treat other psychiatric conditions. Paroxetine is extensively metabolized by cytochrome P450 2D6 (CYP2D6) and variations in CYP2D6 may affect drug exposure. CYP2D6 ultrarapid metabolizers might have lower or undetectable paroxetine plasma concentrations while CYP2D6 poor metabolizers showed greater drug exposure to paroxetine compared to extensive metabolizers at similar drug doses. Therapeutic guidelines for the SSRI paroxetine based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

MedGen UID:
808064
Concept ID:
CN221255
Sign or Symptom
6.

Imipramine response

Imipramine is a tricyclic antidepressant used in the treatment of several psychiatric disorders including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment in the management of panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, a1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, also a tricyclic antidepressant. Further metabolism is catalyzed by CYP2D6. Individuals who are "CYP2D6 ultrarapid metabolizers" carry more than two normal function alleles (i.e., multiple copies), whereas individuals who are "CYP2C19 ultrarapid metabolizers" carry two increased function alleles. Individuals who are CYP2D6 or CYP2C19 "poor metabolizers" carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for imipramine states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. Their recommendations include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6. In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes. Amitriptyline and nortriptyline were used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, it may be reasonable to apply the recommendations to other tricyclics, including imipramine. For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., imipramine) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. [from Medical Genetics Summaries]

MedGen UID:
808063
Concept ID:
CN221257
Sign or Symptom
7.

Statin-induced myopathy

MedGen UID:
507347
Concept ID:
CN181199
Sign or Symptom
8.

Amitriptyline response

Amitriptyline is a tricyclic that can be identified by the tertiary amine in its chemical structure. Tricyclics are commonly prescribed for psychological disorders and pain management. Genetic variants in both cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) may affect treatment success of amitriptyline or other tricyclics with the tertiary amine functional group. Patients with poor metabolizer variants of either CYP2D6 or CYP2C19 may require reductions in dose or alternative agents in order to circumvent common adverse anticholinergic, central nervous system, or cardiac effects. Guidelines regarding the use of pharmacogenomic tests in dosing for amitriptyline and other tricyclics have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

MedGen UID:
500846
Concept ID:
CN176769
Sign or Symptom
9.

Simvastatin response

Statins are among the most commonly prescribed drugs in the world to treat hypercholesterolemia and prevent cardiovascular diseases. They effectively lower cholesterol levels by inhibiting the HMG-CoA reductase to reduce cholesterol synthesis. Though well tolerated in general, the most common statin side effect is muscle pain. The symptoms range from mild muscle pain to fatal rhabdomyolysis, especially when statins are administered at higher doses and with certain other medications. A common coding SNP in the SLCO1B1 gene, rs4149056 or SLCO1B1*5, has been significantly associated with a marked increase in systemic exposure to simvastatin and risk of muscle toxicity. The overall effect size and significance of this association are striking for simvastatin compared to other statins. Patients with this specific variant in SLCO1B1 (a transporter of simvastatin) may require a lower simvastatin dose or consider an alternative statin as compared to patients who do not have this variant, and may consider routine creatine kinase (CK) surveillance. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published a clinical dosing guideline for SLCO1B1 genotype and simvastatin dosing in Clinical Pharmacology & Therapeutics. This guideline is available on the PharmGKB website. [from PharmGKB]

MedGen UID:
472073
Concept ID:
CN128903
Sign or Symptom
10.

Crigler-Najjar syndrome

Crigler-Najjar syndrome is a severe condition characterized by high levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). Bilirubin is produced when red blood cells are broken down. This substance is removed from the body only after it undergoes a chemical reaction in the liver, which converts the toxic form of bilirubin (called unconjugated bilirubin) to a nontoxic form called conjugated bilirubin. People with Crigler-Najjar syndrome have a buildup of unconjugated bilirubin in their blood (unconjugated hyperbilirubinemia).Bilirubin has an orange-yellow tint, and hyperbilirubinemia causes yellowing of the skin and whites of the eyes (jaundice). In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. Severe unconjugated hyperbilirubinemia can lead to a condition called kernicterus, which is a form of brain damage caused by the accumulation of unconjugated bilirubin in the brain and nerve tissues. Babies with kernicterus are often extremely tired (lethargic) and may have weak muscle tone (hypotonia). These babies may experience episodes of increased muscle tone (hypertonia) and arching of their backs. Kernicterus can lead to other neurological problems, including involuntary writhing movements of the body (choreoathetosis), hearing problems, or intellectual disability.Crigler-Najjar syndrome is divided into two types. Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Type 2 (CN2) is less severe. People with CN2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.
[from GHR]

MedGen UID:
468484
Concept ID:
CN119421
Disease or Syndrome
11.

Tramadol response

Tramadol is an analgesic used to treat moderate to moderately severe pain. It is a synthetic opioid, related to codeine, and is used to treat both acute and chronic pain. Tramadol is often prescribed for post-operative pain, and pain caused by cancer, osteoarthritis, and other musculoskeletal diseases. The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including tramadol. Individuals who carry two inactive copies of CYP2D6 are known as poor metabolizers and have higher plasma concentrations of tramadol compared with individuals who have two copies of normal activity alleles. Individuals who carry one or more reduced or inactive copies of CYP2D6 are known as intermediate metabolizers, and individuals who carry more than two active copies of CYP2D6 are known as ultrarapid metabolizers. The FDA states that the levels of tramadol are approximately 20% higher in poor metabolizers compared to extensive (“normal”) metabolizers, while concentrations of the tramadol metabolite, M1, are 40% lower. Inhibitors of CYP2D6, such as fluoxetine and amitriptyline, also inhibit the metabolism of tramadol, and the full pharmacological impact of these alterations of tramadol dose in terms of either efficacy or safety is unknown. A guideline from the Dutch Pharmacogenetics Working Group includes dose recommendations for poor metabolizers (either select an alternative drug—not oxycodone or codeine—or be alert to the symptoms of insufficient pain relief). It also contains dose recommendations for intermediate metabolizers (be alert to decreased efficacy of tramadol, consider increasing the dose and if the response is still inadequate, either select an alternative drug—not oxycodone or codeine, or be alert to the symptoms of insufficient pain relief) and ultrarapid metabolizers (either reduce the dose of tramadol by 30% and be alert to adverse drug events, or select an alternative drug e.g., acetaminophen, NSAID, morphine—not oxycodone or codeine). [from Medical Genetics Summaries]

MedGen UID:
450495
Concept ID:
CN078023
Sign or Symptom
12.

Thioridazine response

Thioridazine is an antipsychotic used in the treatment of schizophrenia and psychosis. Its use is reserved for patients who have failed to respond to or cannot tolerate other antipsychotics. Thioridazine has been shown to prolong the QT interval (the time taken for the heart ventricles to depolarize and repolarize) in a dose related manner. Drugs with this potential have been associated with the life-threatening ventricular tachycardia, "torsades de pointes". The CYP2D6 enzyme is involved in metabolizing thioridazine. About 7% of the population has reduced enzyme activity because of variants in the CYP2D6 gene. In individuals with low CYP2D6 activity, standard doses of thioridazine may lead to higher drug levels in the plasma, and increase the risk of cardiac arrhythmias. The FDA-approved drug label for thioridazine states that thioridazine is contraindicated in individuals who are known to have reduced levels of CYP2D6 activity. The label also states it is contraindicated to coadminister thioridazine with drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) or inhibit the metabolism of thioridazine (e.g., fluvoxamine, propranolol, and pindolol). [from Medical Genetics Summaries]

MedGen UID:
450490
Concept ID:
CN078018
Sign or Symptom
13.

Tamoxifen response

Tamoxifen is a selective estrogen receptor modulator (SERM) which is used in the treatment and prevention of breast cancer . The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, and is one of the main enzymes responsible for converting tamoxifen into its major active metabolite, endofixen. Variants in the CYP2D6 allele may lead to reduced (“intermediate metabolizer”) or absent (“poor metabolizer”) enzyme activity. Individuals who carry these variant alleles may have reduced plasma concentrations of endoxifen and benefit less from tamoxifen therapy. At this time, the FDA-approved drug label for tamoxifen does not discuss genetic testing for CYP2D6. The National Comprehensive Cancer Network (NCCN) does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy, and this recommendation is consistent with the 2010 guidelines from the American Society of Clinical Oncology (ASCO). In contrast, the Dutch Pharmacogenetics Working Group has made recommendations for tamoxifen therapy based on CYP2D6 genotypes. For both poor and intermediate metabolizers, their recommendation is to consider using aromatase inhibitors for postmenopausal women due to an increased risk for relapse of breast cancer with tamoxifen. They also recommend that intermediate metabolizers avoid the concomitant use of CYP2D6 inhibitors. [from Medical Genetics Summaries]

MedGen UID:
450485
Concept ID:
CN078013
Sign or Symptom
14.

Irinotecan response

Irinotecan is a topoisomerase inhibitor that is widely used in the treatment of cancer. It is often used in combination with other drugs to treat metastatic colorectal cancer. However, irinotecan therapy is associated with a high incidence of toxicity, including severe neutropenia and diarrhea. Irinotecan is metabolized and inactivated by an UDP-glucuronosyltransferase enzyme encoded by the gene UGT1A1. UDP-glucuronosyltransferase enzymes are part of the glucuronidation pathway that transforms small lipophilic molecules, such as certain drugs like irinotecan, into water-soluble, excretable metabolites. Variants of this gene, such as UGT1A1*28, are associated with reduced enzyme activity and an increased risk of irinotecan toxicity. Approximately 10% of North Americans are homozygous for the UGT1A1*28 allele and are more likely to develop neutropenia following irinotecan therapy. The FDA-approved drug label for irinotecan states that "when administered as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment". A guideline from the Dutch Pharmacogenetics Working Group (KNMP) mentions "although results are not consistent, there is sufficient evidence that a reduction in the initial dose by 30% is required for regimens containing >250 mg/m2 of irinotecan prescribed to homozygous carriers of the UGT1A1*28 allele. This is in agreement with the Food and Drug Administration–mandated label change. No dose reduction is recommended for heterozygous carriers of the UGT1A1*28 allele because dose reduction might result in under treatment". A guideline from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group (published in 2009, prior to the FDA statement or KNMP guideline) states that "the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia)". [from Medical Genetics Summaries]

MedGen UID:
450461
Concept ID:
CN077989
Sign or Symptom
15.

Esomeprazole response

Esomeprazole blocks the secretion of gastric acid and belongs to the drug class of proton pump inhibitors. It is used to treat gastroesophageal reflux disease (GERD) and to reduce the risk of gastric ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). Esomeprazole is also used in the treatment of hypersecretory conditions, such as Zollinger-Ellison syndrome, and is used in combination with antibiotics to eradicate Helicobacter pylori (H. pylori) infection. Esomeprazole is metabolized primarily by the CYP2C19 enzyme. Approximately 3% of Caucasians and 15 to 20% of Asians have reduced or absent CYP2C19 enzyme activity ("poor metabolizers"). In these individuals, standard doses of esomeprazole leads to higher exposure of the drug. In contrast, individuals with increased CYP2C19 activity ("ultrarapid metabolizers") may be exposed to lower levels of esomeprazole and have an insufficient response to treatment. The FDA-approved drug label for esomeprazole states that poor metabolizers are exposed to approximately twice the level of drug compared to the rest of the population ("extensive metabolizers"), but the label does not require dose changes for poor metabolizers. However, the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) has published dose alterations based on CYP2C19 genotype. For CYP2C19 poor metabolizers, they do not recommend altering the dose; however for ultrarapid metabolizers, they recommend being extra alert to an insufficient response to treatment. For the eradication of H. pylori in ultrarapid metabolizers, KNMP recommends increasing the dose of omeprazole by 50–100%, and to consider the same dose increase for other conditions. [from Medical Genetics Summaries]

MedGen UID:
450454
Concept ID:
CN077982
Sign or Symptom
16.

Doxepin response

Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants. [from Clinical Pharmacogenetics Implementation Consortium]

MedGen UID:
450450
Concept ID:
CN077978
Sign or Symptom
17.

Clozapine response

Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 (poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. [from Medical Genetics Summaries]

MedGen UID:
450443
Concept ID:
CN077971
Sign or Symptom
18.

Disorder due cytochrome p450 CYP2D6 variant

MedGen UID:
449534
Concept ID:
C1827409
Disease or Syndrome
19.

Crigler-Najjar syndrome, type II

The hereditary hyperbilirubinemias (Wolkoff et al., 1983) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I, and Crigler-Najjar syndrome type II; and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (237500), Rotor syndrome (237450), and several forms of intrahepatic cholestasis (147480, 211600, 214950, 243300). Detailed studies show that patients with Crigler-Najjar syndrome type II have reduced activity of bilirubin glucuronosyltransferase (Labrune et al., 1989, Seppen et al., 1994). [from OMIM]

MedGen UID:
419718
Concept ID:
C2931132
Disease or Syndrome
20.

Colchicine resistance

MedGen UID:
396151
Concept ID:
C1861502
Disease or Syndrome
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