Table 3.
List of Genes and Reference SNPs (Rs: Reference Sequences) Associated with Drug Effects. Study Annotation Based on Data from Pharmgkb.org HGVS: Human Genome Variation Society (http://varnomen.hgvs.org)
| Drug/biological Agent | Enzyme Involved | Genetic Variant HGVS Name | Reference SNP | Clinical Annotation | PharmGKB ID | Reference |
|---|---|---|---|---|---|---|
| Antiretrovirals | UGT1A1 | c.*238-6785_*238-6786insTA | rs8175347 | Patients with the (TA)6/(TA)7 (UGT1A1*1/*28) or (TA)7/(TA)7 (UGT1A1*28/*28) genotype have increased levels of bilirubin leading to an increased likelihood for hyperbilirubinemia when treated with atazanavir and ritonavir. | 982047507 | 40 |
| c.*339G>C | rs1042640 | Patients with the GG genotype may be at increased risk of nephrolithiasis when treated with atazanavir and ritonavir as compared to patients with the CG or CC genotypes. | 1185000362 | 41 | ||
| c.*440G>C | rs8330 | Patients with the GG genotype may be at increased risk of nephrolithiasis when treated with atazanavir and ritonavir as compared to patients with the CG or CC genotypes. | 1185000369 | 41 | ||
| c.*211T>C | rs10929303 | Patients with the TT genotype may be at increased risk of nephrolithiasis when treated with atazanavir and ritonavir as compared to patients with the CC or CT genotypes. | 1185000350 | 41 | ||
| c.*238-7110C>T | rs887829 | Patients with the CC or CT genotype who are treated with atazanavir may have a decreased risk of hyperbilirubinemia and bilirubin-related drug discontinuation compared to patients with the TT genotype. | 1183863836 | 44 | ||
| UGT1A7 | c.391C>A | rs17863778 | Patients with the AA genotype may be more likely to develop hyperbilirubinemia when administered atazanavir and ritonavir as compared to patients with the AC or CC genotypes. Please note: the AA genotype was significantly associated with likelihood of hyperbilirubinemia only when it was part of a haplotype with four other UGT1A variants: rs7586110 GG, rs17868323 GG (UGT1A7), rs3806596 CC (UGT1A3), and UGT1A1*28/*28. | 1448097587 | 45 | |
| c.855+44504T>G | rs7586110 | Patients with the GG genotype may be more likely to develop hyperbilirubinemia when administered atazanavir and ritonavir as compared to patients with the GT or TT genotypes. Please note: the GG genotype was significantly associated with likelihood of hyperbilirubinemia only when it was combined with the rs17868323 GG, rs17863778 AA (UGT1A7), rs3806596 CC (UGT1A3), and UGT1A1*28/*28 genotypes. | 1448097556 | 46 | ||
| c.387T>G | rs17868323 | Patients with the GG genotype may be more likely to develop hyperbilirubinemia when administered atazanavir and ritonavir. Please note: the GG genotype was significantly associated with likelihood of hyperbilirubinemia only when it was combined with the rs7586110 GG and rs17863778 AA (UGT1A7), rs3806596 CC (UGT1A3), and UGT1A1*28/*28. | 1448097574 | 46 | ||
| UGT1A3 | c.*237+11029T>C | rs3806596 | Patients with the CC genotype may be more likely to develop hyperbilirubinemia when administered atazanavir and ritonavir. Please note: the CC genotype was significantly associated with likelihood of hyperbilirubinemia only when it was part of a haplotype with 4 other UGT1A variants: rs17868323 GG and rs17863778 AA, rs7586110 GG (UGT1A7), and UGT1A1*28/*28. | 1448097600 | 46 | |
| APOE | c.466T>C | rs429358 | Patients with the CC or CT genotype who are treated with antiretrovirals such as ritonavir or combinations may be at increased risk for elevated plasma lipids compared to patients with the TT genotype. | 655384666 | 47 | |
| c.604C>T | rs7412 | Patients with the TT or CT genotype may be at increased risk of elevated triglycerides in response to ritonavir containing antiretroviral therapy compared to patients with the CC genotype. Patients with the TT or CT genotype who are treated with antiretroviral regimens containing ritonavir may be at increased risk of hypertriglyceridemia compared to patients with the CC genotype. | 981203709 | 47 | ||
| Antiretrovirals | APOC3 | Regulatory region variant g.116829426T>C | rs2854117 | Patients with the TT or TC genotype who are treated with ritonavir may have higher triglyceride levels (increased risk of hypertriglyceridemia) than patients with the CC genotype. | 655385082 | 47 |
| Regulatory region variant g.116829453C>T | rs2854116 | Patients with the TT genotype who are treated with ritonavir may have increased severity of triglyceride elevation as compared to patients with the CT or TT genotypes. | 655385087 | 48 | ||
| c.*40G>C | rs5128 | Patients with the CC genotype who are treated with ritonavir may be at increased risk of triglyceride elevation as compared to patients with the CG or GG genotypes. | 655385092 | 48 | ||
| ABCC2 | c.-24C>T | rs717620 | Patients with the TT or CT genotype who are treated with atazanavir, lopinavir, ritonavir, or tenofovir may be at increased risk for drug toxicity compared to patients with the TT genotype. | 1447982779 | 49 | |
| c.4544G>A | rs8187710 | Patients with the AA or AG genotype who are treated with lopinavir may have a higher accumulation of lopinavir in peripheral blood mononuclear cells and reduced ABCC2-mediated efflux of lopinavir compared to patients with the GG genotype. | 1183491026 | 50 | ||
| ABCB1 | c.3243A>G | rs1045642 | Patients with the AG or GG genotype may be at increased risk of virological failure when receiving highly active antiretroviral therapy (HAART), with lamivudine, lopinavir, ritonavir or zidovudine as compared to patients with the AA genotype. | 1183690892 | 51 | |
| ABCC1 | c.*1512T>C | rs212091 | Patients with the CC or CT genotype may be at increased risk of virological failure when treated with highly active antiretroviral therapy (HAART) with lamivudine, lopinavir, ritonavir, or zidovudine compared to patients with the TT genotype. | 1444673130 | 51 | |
| ITPA | c.124+21A>C | rs7270101 | Patients with the AA genotype may be at increased risk of anemia but a decreased risk of thrombocytopenia compared to patients with the AC and CC genotype who are taking PEG-IFN-IFNα2b and ribavirin. Studies have looked at the composite genotypes of rs1127354 CC and rs7270101 AA to identify “normal” vs “deficient” ITPase activity. Normal ITPase activity is associated with increased risk of anemia and possibly decreased risk of thrombocytopenia compared to deficient activity. Patients with the CC or AC genotype may be at decreased risk of anemia but at increased risk of thrombocytopenia. | 1446905703 | 38 | |
| c.43C>A | rs1127354 | Patients with the AA or AC may be at decreased risk of anemia but at increased risk of thrombocytopenia when compared to patients with the CC genotype. Patients with the chronic CC genotype may be at increased risk of anemia. but at decreased risk of thrombocytopenia. | 1446905691 | 38 | ||
| c.2651–716A>C | rs6051702 | Patients with the AA genotype who are treated with ribavirin may be at increased risk of anemia as compared to patients with the CC or AC genotype. | 1444703777 | 38 | ||
| VDR | c.*1026+283G>A | rs1544410 | Patients with the AA genotype may be at increased risk of anemia when treated with PEG-IFNα2a and ribavirin compared to patients with the GG or GA | 1444700867 | 38 | |
| c.152A>G | rs2228570 | Patients with the AA or AG genotype may have an increased likelihood of sustained virological response when treated with PEG-IFNα2b and ribavirin compared to patients with the GG genotype. | 1448102550 | 38 | ||
| SLC28A2 | c.65C>T | rs11854484 | Patients with the TT genotype may be at increased risk of anemia when treated with protease inhibitors plus ribavirin and PEG-IFN compared to patients with the CC or CT genotype. | 1445401427 | 38 | |
| Antiretrovirals | IFNL3 | Intergenic variant g.39241861T>C | rs8105790 | Patients with the TT genotype may have increased likelihood of sustained virological response when treated with PEG-IFNα and ribavirin compared to patients with the CC or CT genotype. | 1448102470 | 38 |
| c.*52G>T | rs4803217 | Patients with the TT genotype may have higher response rates (SVR) to triple therapy (telaprevir, PEG-IFNα2a/b and ribavirin) than patients with the GG or GT genotype. | 1448102490 | 38 | ||
| Intergenic variant g.39253181G>A | rs7248668 | Patients with the GG genotype may have an increased likelihood of sustained virological response when treated with PEG-IFNα and ribavirin as compared to patients with the AA or AG genotype. | 1448102463 | 50 | ||
| MICB | c.27+3023C>A | rs3828913 | Patients with genotype CC may have higher rate of sustained virological response (SVR) treated with PEG-IFN plus ribavirin (PEG-IFN/RBV) therapy as compared to patients with genotype AA or AC. | 1444843493 | 38 | |
| OASL | c.1509C>T | rs12819210 | Patients with the TT genotype may have increased SVR (sustained virological response) when treated with PEG-IFNα2b and ribavirin compared to patients with the CC or CT genotype. | 1183680570 | 38 | |
| SCARB1 | c.127–10172C>G | rs10846744 | Patients with the CC or CG genotype may have increased sustained virological response (SVR) when treated with peginterferon alpha and ribavirin as compared to patients with genotypes GG. | 1448264186 | 38 | |
| SLC29A1 | c.1260–201A>G | rs760370 | Patients with the GG genotype may be more likely to have rapid virological response when treated with pegylated interferon-ribavirin therapy as compared to patients with the AA or AG genotype. | 1448101202 | 38 | |
| ND3 | c.340A>G | rs2853826 | Patients with the G allele may have a greater decline in adiponectin when treated with antiretroviral therapy (lopinavir, Nucleoside and nucleotide reverse transcriptase inhibitors or ritonavir)as compared to patients with the A allele. | 1447963057 | 38 | |
| CYP3A4 | Intergenic variant g.99784473C>T |
rs2740574 | Patients with the CC or CT genotype may have decreased clearance of atazanavir as compared to patients with the TT genotype. | 1448617757 | 53 | |
| SLCO3A1 | c.646+25149G>T | rs8027174 | Genotypes GG is associated with increased clearance of darunavir in people as compared to genotypes GT + TT. | 1184137368 | 55 | |
| Interferon-α and –β | GAPVD1 | c.*3757A>G | rs2291858 | Patients with the AA or AG genotype may have a decreased response to treatment with interferon-beta as compared to patients with the GG genotype. | 1447959738 | 55 |
| c.-150+13007C>T | rs10819043 | Patients with the CC genotype may have a decreased response to treatment with interferon-beta as compared to patients with the TT genotype. | 1447959731 | 55 | ||
| g.125370928T>C | rs10760397 | Allele C is associated with increased response to interferon beta-1a and interferon beta-1b in as compared to allele T. | 1447959700 | 55 | ||
| NONE | intergenic variant g.17565446A>G |
rs1448673 | Patients with the AA genotype may have a decreased response to treatment with interferon-beta as compared to patients with the GG or AG genotype. | 1447959724 | 55 | |
| IRF6 | c.-307+4490G>A | rs2205986 | Patients with the AG or GG genotype may be at increased risk of developing drug-induced liver injury following treatment with interferon beta as compared with the AA genotype. | 1449713231 | 56 | |
| Interferon-α and –β | CD58 | c.71–553G>T | rs12044852 | Patients with the AA or AC may have a better response to treatment with interferon beta 1a/1b as compared to patients with the CC genotype. | 1445402209 | 57 |
| NONE | Regulatory region variant g.126157578A>G |
rs3133084 | Patients with the AA or AG genotype may have an increased response to treatment with interferon-beta as compared to patients with the GG genotype. | 1447959752 | 55 | |
| ZNF697 | Regulatory region variant g.119594822A>G | rs10494227 | Patients with the AA or AG genotype may have an increased response to treatment with interferon-beta as compared to patients with the GG genotype. | 1447959700 | 55 | |
| FHIT | c.104–99089C>T | rs760316 | Patients with the CC genotype may have an increased response to treatment with interferon-beta as compared to patients with the TT genotype. | 1447959717 | 55 | |
| Tocilizumab | IL6R | c.1067–5190T>C | rs4329505 | Patients with the TT genotype who are treated with tocilizumab may have increased response to tocilizumab as compared to patients with the CT or TT genotypes. | 1444704366 | 38 |
| IL6R | c.85+2913A>G | rs12083537 | Patients with the AG genotype who are treated with tocilizumab may have increased response to tocilizumab as compared to patients with the AA or GG genotypes. | 1444700767 | 38 | |
| IL6R | c.1067–7518C>T | rs11265618 | Patients with the CC genotype may have a better response when treated with tocilizumab as compared to patients with the CT or TT genotypes. | 1448112486 | 38 | |
| CD69 | c.*387T>C | rs11052877 | Patients with the AA or AG genotype may have an increased response to tocilizumab compared to patients with the GG genotype. | 1448112486 | 38 | |
| FCGR3 | c.526T>A | rs396991 | Patients with AA genotype may have an increased response to tocilizumab as compared to patients with the AC or CC genotypes. | 1450371701 | 38 | |
| GALNT18 | c.236–9383G>A | rs4910008 | Patients with CC genotype may have an increased response to tocilizumab as compared to patients with the CT or TT genotypes. | 1448112493 | 38 | |
| Bevacizumab | HSP90AB1 | Regulatory region variant g.44235246A>G | rs6929249 | Patients with the AG or GG genotype may be at increased risk of developing hypertension as a result of bevacizumab treatment as compared to patients with the AA genotype. | 1449564196 | 58 |
| HSP90AB1 | Regulatory region variant g.44238042C>A |
rs834576 | Patients with the AA or AC genotype may be at increased risk of developing hypertension as a result of bevacizumab treatment as compared to patients with the CC genotype. | 1449564202 | 58 | |
| PRKCA | Intergenic variant g.44244130T>C | rs9381299 | Patients with the CC genotype be at increased risk of developing hypertension as a result of bevacizumab treatment as compared to patients with the TT genotype. | 1449564208 | 58 | |
| HSP90AB1 | TF-binding site g.44234210A>C | rs3734704 | Patients with the CC genotype be at increased risk of developing hypertension as a result of bevacizumab treatment as compared to patients with the AA genotype. | 1449564190 | 58 | |
| Hydrocortisone Prednisolone Dexamethasone |
ATF5 | c.*22G>A prime UTR variant |
rs8667 | Genotypes AA + AG is associated with increased likelihood of diarrhea when treated with asparaginase, cytarabine, hydrocortisone and prednisone as compared to genotype G. | 1450044679 | 59 |
| MIR3683 | Noncoding transcript-exon variant g.7067005A>G |
rs6977967 | Genotype GG is associated with increased likelihood of mucositis when treated with asparaginase, cyclophosphamide, cytarabine, daunorubicin, hydrocortisone, prednisone and vincristine as compared to genotypes AA + AG. | 1450044669 | 59 | |
| CTNNB1 | Intergenic variant g.203866282A>G |
rs4553808 | Patients with the AA who are treated with dexamethasone and prednisone may have a later onset of bortezomib-induced peripheral neuropathy as compared to patients with the AG or GG genotype. | 1043880851 | 60 | |
| PNPLA3 | c.432C>G | rs738409 | Patients with the CG genotype may have increased risk of hepatotoxicity when treated with remission induction therapy as compared to patients with genotype CC. | 1448632697 | 61 | |
| Captopril | ACE | Intron variant c.584–105_584-104ins |
rs1799752 | Patients with the ATACAGTCACTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC/del genotype and conditions such as heart failure, chronic obstructive pulmonary disease and Type 2 diabetes may have an increased response when treated with captopril as compared to patients with the del/del genotype, or a decreased response compared to patients with the ATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC/ATACAGTCACTTTTTTTTTTTTTTGGACACGGAGTCTCGCTCTGTCGCCC genotype. Responses were also tested within healthy individuals in one study | 982047862 | 62 |
| Regulatory region variant g.63476833T>A |
rs4291 | Patients with the AA genotype not experience increasing creatinine levels when taking captopril compared to patients with the AT and TT genotypes. | 1448259106 | 62 | ||
| ACE2 | c.*264+788A>G | rs2106809 | Patient with the AA and AG genotype and hypertension may have a smaller decrease in diastolic blood pressure when treated with captopril as compared to patient with the GG genotype. | 1183612731 | 62 | |
| AGTR1 | c.*86A>C | rs5186 | Patients with the CC and CA genotype have an increased response when treated with captopril as compared to patients with the AA genotype. | 1043858965 | 62 |
Notes: This table shows all drugs and biological agents considered in our study, and for each the genes and respective sequence variants of pharmacogenetic interest have been listed. All variants were named following the sequence-variant nomenclature suggested by the Human Genome Variation Society (http://varnomen.hgvs.org).42 Each variant report show the reference SNP (refSNP) cluster ID numbers (rs#), a code by which each SNP can be queried from the dbSNP website (https://www.ncbi.nlm.nih.gov/snp) and through which further information is available (such as functional analysis, population-specific allele frequencies, validation information, or clinical significance).43 Furthermore, for each variant, a summary of PharmGKB clinical annotations with respective identification codes (phenotype for any given genotype) is reported. Using the access codes for dbSNP and PharmGKB, it is thus possible to find more information for the sequence variants and the respective variant-drug responsiveness associations. Finally, the last columnshows the most significant bibliographic reference concerning the association between the genetic variant reported and individual drug responsiveness.