Table 1.
PharmGKB criteria for levels of evidence
| Level | Criteria | Example |
|---|---|---|
| 1A | Annotation for a variant– drug combination in a CPIC- or medical society–endorsed pharmacogenomics guideline, or implemented at a PGRN site, or in another major health system | rs1800460 in TPMT (TPMT*3B)a and thiopurines: This association is published as a CPIC guideline and used in multiple clinics Drugs: azathioprine, mercaptopurine, purine analogues, thioguanine CC: Patients with the CC genotype may have a decreased, but not absent, risk for toxicity with thiopurine drugs and purine analogues as compared to patients with the CT or TT genotype. Patients with the CC genotype may still be at risk for toxicity when taking thiopurine drugs and purine analogues based on their genotype. Other genetic and clinical factors may also influence a patient’s risk for toxicity CT: Patients with the CT genotype may have an increased risk for toxicity with thiopurine drugs and purine analogues as compared to patients with the CC genotype. Other genetic and clinical factors may also influence a patient’s risk for toxicity TT: Patients with the TT genotype may have an increased risk for toxicity with thiopurine drugs and purine analogues as compared to patients with a CC genotype. Other genetic and clinical factors may also influence a patient’s risk for toxicityb |
| 1B | Annotation for a variant–drug combination in which the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant P values, and, preferably with a strong effect size | rs1801133 in mthfr and methotrexate: PharmGKB has multiple articles for this association with significant P values and several with high odds ratios Drug: methotrexate AA: Patients with the AA genotype with leukemia or lymphoma who are treated with methotrexate regimens may have an increased risk and increased severity of mucositis, as compared to patients with the GA or GG genotype. Other genetic and clinical factors may also influence a patient’s risk of oral mucositis AG: Patients with the AG genotype with leukemia or lymphoma who are treated with methotrexate regimens may have a decreased risk and decreased severity of mucositis as compared to patients with the AA genotype. Other genetic and clinical factors may also influence a patient’s risk of oral mucositis GG: Patients with the GG genotype with leukemia or lymphoma who are treated with methotrexate regimens may have a decreased risk and decreased severity of mucositis as compared to patients with the AA genotype. Other genetic and clinical factors may also influence a patient’s risk of oral mucositis |
| 2A | Annotation for a variant–drug combination that qualifies for level 2B, in which the variant is within a VIP as defined by PharmGKB where their functional significance is more likely known | rs12248560 in CYP2C19 and omeprazole: PharmGKB has multiple articles for this association, and it qualifies for level 2 and is in a pharmacogene Drug: omeprazole CC: Adult patients with the CC genotype who are treated with omeprazole may require a decreased dose as compared to patients with the TT genotype. Other genetic factors, including other CYP2C19 alleles *17 rs12248560, *2 rs4244285, *3 rs4986893, and clinical factors may also influence a patient’s required dose and should be taken into consideration. May not be applicable to pediatric patients CT: Patients with this genotype were not studied TT: Adult patients with the TT genotype who are treated with omeprazole may require an increased dose as compared to patients with the CC genotype. Other genetic factors, including other CYP2C19 alleles *17 rs12248560, *2 rs4244285,*3 rs4986893, and clinical factors may also influence a patient’s required dose and should be taken into consideration. May not be applicable to pediatric patientsd |
| 2B | Annotation for a variant–drug combination with moderate evidence of an association. The association must be replicated, but there may be some studies that do not show statistical significance, and/or the effect size may be small | rs2234922 in EPHX1 and carbamazepine: PharmGKB contains two articles with significant P values, one with no association reported; population sizes ranging from 70 to 234; no odds ratios reported Drug: carbamazepine AA: Patients with the AA genotype may require a decreased dose of carbamazepine as compared with patients with the AG or GG genotype. Other genetic and clinical factors may also influence dose of carbamazepine AG: Patients with the AG genotype may require an increased dose of carbamazepine as compared with patients with the AA genotype. Other genetic and clinical factors may also influence dose of carbamazepine GG: Patients with the GG genotype may require an increased dose of carbamazepine as compared with patients with the AA genotype. Other genetic and clinical factors may also influence dose of carbamazepinee |
| 3 | Annotation for a variant–drug combination based on a single significant (not yet replicated) study or annotation for a variant–drug combination evaluated in multiple studies but lacking clear evidence of an association | rs993648 in CERKL and iloperidone: PharmGKB contains a genome-wide association study article reporting a statistically significant association, but it is not replicated Drug: iloperidone CC: Patients with the CC genotype who are treated with iloperidone may have an increased risk for adverse cardiovascular events as compared with patients with the CT genotype. Other genetic and clinical factors may also influence a patient’s response CT: Patients with the CT genotype who are treated with iloperidone may have a decreased, but not absent, risk for adverse cardiovascular events as compared with patients with the CC or TT genotype. It is unclear at this time why the heterozygous genotype would confer a phenotype different from either homozygous genotype TT: Patients with the TT genotype who are treated with iloperidone may have an increased risk for adverse cardiovascular events as compared with patients with the CT genotype. Other genetic and clinical factors may also influence a patient’s responsef |
| 4 | Annotation based on a case report, nonsignificant study, or in vitro, molecular, or functional assay evidence only | rs61750900 in UGT2B10 and nicotine: PharmGKB contains two in vitro studies for this association Drug: nicotine GG: The GG genotype is not associated with changes in nicotine metabolism/clearance in human liver microsomes from subjects with the GG genotype and HEK293 overexpressing UGT2B10 GT: The GT genotype is significantly associated with a decrease in nicotine metabolism/clearance in human liver microsomes from subjects with the GT genotype as compared with subjects with the GG genotype TT: The TT genotype is significantly associated with a decrease in nicotine metabolism/clearance in human liver microsomes from subjects with the TT genotype as compared with subjects with the GG genotype and HEK293 overexpressing UGT2B10 variant constructg |
CPIC, Clinical Pharmacogenetics Implementation Consortium; PGRN, Pharmacogenomics Research Network; PharmGKB, the Pharmacogenomics Knowledgebase; VIP, very important pharmacogene.
a
PharmGKB reports alleles on the positive chromosomal strand.
Adapted from PharmGKB with the permission of PharmGKB and Stanford University. Copyright PharmGKB.