Table 2.
Selected drug-gene pairs with a guideline recommendation.
| Drug (Clinical use) | Genetic testing indication | Positive genetic test resultsˆ | Negative genetic test resultsˆ | Evidence for clinical utility | Treatment guidance |
|---|---|---|---|---|---|
| Abacavir (1st- line treatment of HIV infection) | Screening to avoid immune-mediated hypersensitivity reactions (occurs in ~6% of pts) | 1-2 copies of HLA-B*57:01 | 0 copies of HLA-B*57:01 | PREDICT-1: NPV=100%, PPV=47.9%, evidence for cost-effectiveness; recommended by FDA 26,30 | PharmGKB GL72; drug contraindicate d for pts w/HLA-B*57:01 |
| Allopurinol (treatment of gout) | Screening to avoid severe cutaneous adverse reactions | 1-2 copies of HLA-B*58:01 | 0 copies of HLA-B*58:01 | Significantly increased risk (ORs of 80-580) for pts w/ HLA-B*58:01 variant48-53 | PharmGKB GL73; drug contraindicate d for pts w/ HLA-B*58:01 |
| Atazanavir (antiretroviral protease inhibitor) | Screening for drug-related jaundice | Intermed metabolizer: presence of 1 UGT1A1 decreased-function allele (*6, *28, *37) w/ UGT1A1*1 (normal function) or UGT1A1*36 (increased function), 1 copy of rs887829 T allele; poor metabolizer: 2 decreased-function alleles (UGT1A1*6, *28, *37) or 2 copies of rs887829 T alleles | UGT1A1*1/*1; *1/*36; *36/*36; rs887829 C/C | AIDS Clinical Trials Group protocol A5257: high likelihood of developing jaundice resulting in atazanavir discontinuation w/ UGT1A1 poor metabolizers 54,55 | PharmGKB GL74 |
| Azathioprine (immunosuppr essant used in solid organ transplant & immunological disorders) | Dose adjustment for variants related to low or deficient drug metabolism | TPMT intermed activity (3%-14% of pts): 1 functional allele (*1) + 1 nonfunctional allele (*2, *3A, *3B, *3C, *4); low/deficient activity (1 in 178-3,736 pts): 2 nonfunctional alleles (*2, *3A, *3B, *3C, *4) | TPMT*1/*1 | Substantial evidence that dose adjustments based on TPMT reduce adverse effects w/out compromising desired therapeutic effects 56 | PharmGKB GL75 |
| Carbamazepin e (anticonvulsan t, also used in trigeminal neuralgia) | Screening for Steven-Johnson syndrome & toxic epidermal necrolysis | 1-2 copies of HLA-B*15:02 | 0 copies of HLA-B*15:02 | Significant association of HLA-B*15:02 genotype in pts w/ Asian ancestry w/ carbamazepine-induced Steven-Johnson syndrome & toxic epidermal necrolysis vs carbamazepine-tolerant pts & healthy controls 34 | PharmGKB GL76; use alt drug for pts testing positive if naïve |
| Clopidogrel (antiplatelet drug) | Screening before percutaneous coronary angioplasty for effectiveness (non-response) | CYP2C19 ultra-rapid metabolizer (~5%-30% of pts): 2 increased-activity alleles (*17) or 1 functional allele (*1) + 1 increased-activity allele (*17); intermed metabolizer (~18%-45% of pts): 1 functional allele (*1) + 1 LOF allele (*2-*8), or 1 LOF allele (*2-*8) + 1 increased-activity allele (*17); poor metabolizer (~2-15% of pts; *4-*8 rarely seen): 2 LOF alleles (*2-*8) | CYP2C19*1/*1 | Substantial literature implicating LOF CYP2C19 alleles in adverse clopidogrel responses, FDA black box warning on drug label 57; TRITON-TIMI 38: vs noncarriers, pts w/ reduced-function CYP2C19 allele have HR of 4.79 (1.40-16.37) for death from CV causes, 1.38 (0.94-2.02) for nonfatal MI, 3.93 (0.66-23.51) for nonfatal stroke, & 3.09 (1.19-8.00) for stent thrombosis 58 | PharmGKB GL77; CYP2C19 ultra-rapid metabolizer: use standard dose; intermed & poor metabolizer: use alt drug |
| Codeine (analgesic) | Screening for efficacy (poor metabolizer, insufficient pain relief) & toxicity (ultra-rapid metabolizer, due to increased metabolism to morphine) | CYP2D6 ultra-rapid metabolizer (~1-2% of pts): 2+ copies of functional alleles (*1/*1xN, *1/*2xN); intermed metabolizer (~2-11% of pts): 1 reduced & 1 nonfunctional allele (*4/*10, *5/*41); poor metabolizer (~5-10% of pts): nonfunctional alleles (*4/*4, *4/*5, *5/*5, *4/*6) | CYP2D6 *1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *10/*10 | Substantial evidence for decreased analgesia in poor metabolizers & severe or life-threatening toxicity following normal doses of codeine in ultrarapid metabolizers 59 | PharmGKB GL78 |
| Ivacaftor (cystic fibrosis treatment) | Screening for drug efficacy (non-response) | 2 copies of CFTR F508del (rs113993960 or rs199826652 genotype del/del) | 0-1 copies of CFTR F508del; 1-2 copies of the following CFTR variantsˆˆ: E56K, P67L, R74W, D110E, D110H, R117C, E193K, L206W, R347H, R352Q, A455E, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, D1270N, G551D | CFTR F508del 2 copies: no significant reduction in sweat chloride concentrations, drug provides no clinical & lung function improvement 23; G551D/G551D or G551D/F508del: improvement of lung function, weight, risk of pulmonary exacerbation, & reduction in sweat chloride concentrations w/ drug use; moderate evidence for improvement w/ 1+ copy of variants inˆˆ except G551D | PharmGKB GL79; 2 copies of CFTR F508del: ivacaftor not recommended ; G551D/G551 D or G551D/F508d el: ivacaftor recommended |
| Phenytoin (anticonvulsan t) | Screening to avoid cutaneous adverse reactions of Stevens-Johnson syndrome & toxic epidermal necrolysis | 1-2 copies of HLA-B*15:02; CYP2C9 intermed metabolizer (~8% of pts): *1/*2, *1/*3; CYP2C9poor metabolizer (~1% of pts): *2/*2, *3/*3, *2/*3 | 0 copies of HLA-B*15:02; CYP2C9*1/*1 | Significantly increased risk of Steven-Johnson syndrome & toxic epidermal necrolysis w/ HLA-B*15:02 variant in Asian groups (OR, 4.26 [1.93-9.39])60,61; phenytoin maintenance doses reduced by 23%-38% in heterozygous pts & by 31-52% in homozygous pts for decreased-function CYP2C9 alleles62-64 | PharmGKB GL80; HLA-B*15:02: drug contraindicated for phenytoin-naïve pts |
| Simvastatin (lipid-lowering drug) | Screening to avoid simvastatin-induced myopathy (myalgias occur in 1-5% of exposed pts) | Intermed function in plasma clearance of simvastatin: 1 copy of decreased-function allele of SLCO1B1 (*5, *15, *17) or rs4149056 T/C; low function: 2 copies of SLCO1B1*5, *15, *17 or rs4149056 C/C | Normal function: SLCO1B1*1a/*1a, *1a/*1b, *1b/*1b or rs4149056 T/T | RCT (SEARCH) & clinical practice-based cohorts (HPS): ORs for myopathy of 4.5 & 2.6, respectively, per copy of the minor C rs4149056 allele w/ simvastatin (less evidence for other statins); STRENGTH: highest overall effect size of drug discontinuation for any adverse effect, myalgia, muscle cramping, or elevated serum CK levels >3-fold of ULN for simvastatin (OR 2.8 [1.3-6.0]) compared to atorvastatin (OR 1.6 [0.7-3.7]) or pravastatin (OR 1.06 [0.22-4.8])65-68 | PharmGKB GL81 |
| Tacrolimus (immunosuppr essant) | Dose adjustments for variants related to enzyme expression | CYP3A5 extensive metabolizer: *1/*1; intermed metabolizer: *1/*3, *1/*6, *1/*7 | CYP3A5 poor metabolizer: *3/*3, *6/*6, *7/*7, *3/*6, *3/*7, *6/*7 | Strong evidence based on more than 50 studies for use of tacrolimus in kidney, heart, lung, HSCT, & liver Tx pts where the donor & recipient genotypes are identical; 69 ongoing clinical trials: ClinicalTrials.gov | PharmGKB GL82 |
| Warfarin (oral anticoagulant) | Dose adjustment & efficacy based on metabolism (CYP2C9) & sensitivity (VKORC1) | Non-African ancestry: CYP2C9*2/*3, *3/*3 (poor metabolizer) or both increased sensitivity (VKORC1 1639 A/A or A/G) & CYP2C9 poor metabolizer; African ancestry: CYP2C9*5 or *6 or *8 or *11, rs12777823 A/G or A/A, CYP4F2*3 | CYP2C9*1 + 0 copies of other alleles listed as positive test; 0 copies of CYP2C9 rs12777823 A allele (only in African ancestry); 0 copies of VKORC1 1639 A allele; 0 copies of CYP4F2*3ˆˆˆ | EU-PACT & COAG trials for genotype-guided dose adjustments; GIFT trial showed the effectiveness and safety of genotyped-guided dosing for VTE & major bleeding (27% reduction) 21,70,71 | PharmGKB GL83 |
Footnote: Based on information from the Clinical Pharmacogenetics Implementation Consortium guidelines (CPIC) and PharmGKB. The most updated version of these guidelines can be found at https://cpicpgx.org/guidelines/.
Alt, alternative; NPV, negative predictive value; PPV. Positive predictive value; COAG, Clarification of Optimal Anticoagulation Through Genetics; CV, cardiovascular; HPS, Heart Protection Study; HSCT, hematopoietic stem cell transplant; intermed, intermediate; MI, myocardial infarction; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; STRENGTH, Statin Response Examined by Genetic Haplotype Markers; EU-PACT, European Pharmacogenetics of Anticoagulant Therapy; PREDICT-1, Prospective Randomized Evaluation of DNA Screening in a Clinical Trial; TRITON-TIMI, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction; LOF, loss of function; RCT, randomized controlled trial; Tx, transplant; ULN, upper limit of normal.
Laboratory reporting of genetic variants varies; a positive result would be one guiding treatment modifications, while a negative result would one with no modification in drug regimen needed.
SNP numbers are as follows for the following amino acid changes: E56K (rs397508256), P67L (rs368505753), R74W (rs115545701), D110E (rs397508537), D110H (rs113993958), R117C (rs77834169), E193K (rs397508759), L206W (rs121908752), R347H (rs77932196), R352Q (rs121908753), A455E (rs74551128), D579G (rs397508288), S945L (rs397508442), S977F (rs141033578), F1052V (rs150212784), K1060T (rs397508513), A1067T (rs121909020), G1069R (rs200321110), R1070Q (rs78769542), R1070W (rs202179988), F1074L (rs186045772), D1152H (rs75541969), D1270N (rs11971167), G551D (rs75527207)
additional variants need to be genotyped in those of African ancestry