Table 1. Significant (p<0.05) variant annotations assigned to INH, RIF, PZA and EMB, according to TBGxforAfrica Application39.
| Gene | Level of evidence | SNP | Impact/phenotype (drug) | No of studies | Significance range (p) | Populations | Reference |
|---|---|---|---|---|---|---|---|
| AADAC | rs1803155 | Reduced exposure (RIF) | 1 | 0.03 | African | 40 | |
| SLCO1B1 | 3 | rs11045819 | Altered clearance (RIF) | 1 | 0.0009 | African | 41 |
| SLCO1B1 | 3 | SLCO1B1*15 (rs4149056) | ATDILI (RIF) | 1 | 0.007 | Asian | 42 |
| NOS | 3 | rs11080344 | ATDILI (INH, RIF) | 1 | 0.036 | East Asian | 43 |
| NR1I2 | 3 | rs2472677 | Peripheral nervous system (INH, RIF) | 1 | 0.018 | African | 44 |
| NR1I2 | 3 | rs2472677 | Death (INH, RIF) | 1 | 0.007 | African | 44 |
| RIPOR2 | 3 | rs10946739 | ATDILI (RIF) | 1 | 0.0000041 | African | 45 |
| RIPOR2 | 3 | rs10946737 | ATDILI (RIF) | 1 | 0.00000044 | African | 45 |
| CUX2 | 3 | rs7958375 | ATDILI (INH, RIF, EMB, PZN) | 1 | 0.000012 | Sub-Saharan African | 45 |
| TNFa | 3 | rs1800629 | ATDILI (INH, RIF, EMB, PZN) | 1 | 0.034 | East Asian | 46 |
| AGBL4 | 3 | rs393994 | ATDILI (INH, RIF, EMB, PZN) | 1 | 0.0000076 | Sub-Saharan African | 45 |
| AGBL4 | 3 | rs320003 | ATDILI (INH, RIF, EMB, PZN) | 1 | 0.0000083 | Sub-Saharan African | 45 |
| AGBL4 | 3 | rs319952 | ATDILI (INH, RIF, EMB, PZN) | 1 | 0.0000085 | Sub-Saharan African | 45 |
| CYP3A5 | 2 | rs776746 | Reduced BDQ exposure | 1 | 0.0017 | Sub-Saharan African | 12 |
| CYP2B6 | 2 | CYP2B6*6 (rs3745274) | ATDILI | 2 | 0.02 | Asian | 47 |
| SLCO1B1 | 3 | rs4149056 | Altered RIF clearance | 1 | <0.001 | Asians | 42 |
| SLCO1B1 | 3 | rs4149032 | Reduced RIF exposure | 1 | Not reported | Sub-Saharan African | 48 |
| NAT2 | (1–3) varies | NAT2*14 (rs1801279), NAT2*5 (rs1801280), NAT2*6 (1799930), NAT2*7 (rs1799931) | Slow acetylator status (INH toxicity) | 20+ | 0.0001–0.05 | African, Asian European | 49 |
| CYP2E1 | (2–3) varies | rs2031920 | Modifies INH toxic metabolite formation | 10+ | 0.001–0.05 | Asian | 50 |
| GSTM1 | 2–3 | Gene deletion (null genotype) | Increased risk of ATDILI | 10+ | <0.05 | Asian | 51 52 |
| GSTT1 | 2–3 | Gene deletion (null genotype) | Increased risk of ATDILI | 10+ | N/A | Asian | 51 |
| CYP2C9 | 2 | rs9332096 | Drug-induced maculopapular eruption (INH, RIF) | 5+ | 0.022 | Asian | 53 |
| CYP2C19 | 2 | rs4986893 | Drug-induced maculopapular eruption (INH, RIF) | 5+ | 0.042 | Asian | 53 |
| – | – | No well-characterised PG markers currently identified available (CFZ, delamanid (DLM), LFX, LZD) | – | – |
Studies including African populations are indicated in green. While extensive PG associations have been reported for first-line drugs used in DS-TB, evidence for second-line drugs used in MDR-TB remains sparse. Few studies have examined genetic variants affecting metabolism of newer drugs like BDQ. Notably, variants in CYP3A5 and CYP2B6 have been linked to altered BDQ metabolism, yet broader PG data for MDR-TB regimens are lacking—particularly in African populations.
ATDILI, antituberculosis drug-induced liver injury; BDQ, bedaquiline; CFZ, clofazimine; DS-TB, drug-sensitive tuberculosis; EMB, ethambutol; INH, isoniazid; LFX, levofloxacin; LZD, linezolid; MDR-TB, multidrug-resistant tuberculosis; PG, pharmacogenetics; PharmGKB, Pharmacogenomics Knowledge Base; PZA, pyrazinamide; PZN, pyrazinamide; RIF, rifampicin; SNP, single nucleotide polymorphism.