Table 1.
Worldwide allele frequencies of SLC variants associated with clinical drug response or toxicity phenotypes
| Gene (protein) | Variant | Type | MAF (in %) | Association | References | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| NFE | FIN | ASJ | LAT | EAS | SAS | AFR | |||||
| SLC1A1 (EAAC1) | rs2228622:G>A | Synonymous (T138T) | 41.7 | 33.9 | 51.7 | 40.7 | 24.6 | 33.9 | 21.2 | Increased risk of antipsychotics-induced obsessive-compulsive symptoms (OR = 3.9) | Kwon et al. (2009) |
| SLC11A1 (NRAMP1) | rs17235409:G>A | Missense (D543 N) | 2.0 | 2.2 | 1.4 | 11.3 | 14.1 | 5.4 | 6.3 | Increased risk of failure of tuberculosis therapy (OR = 11) | Salinas-Delgado et al. (2015) |
| SLC12A3 (NCC) | rs1529927:G>C | Missense (A264G) | 3.6 | 3.1 | 0.6 | 0.6 | 0.0 | 0.8 | 0.6 | Increased efficacy of diuretics | Vormfelde et al. (2007) |
| SLC12A6 (KCC3) | rs7164902:C>T | Synonymous (L159L) | 24.3 | 18.1 | 25.1 | 18.3 | 34.2 | 34.0 | 21.6 | Decreased risk of thalidomide-induced neuropathy (OR = 0.5–0.6) | Johnson et al. (2011) |
| SLC15A2 (PEPT2) | rs1143671:C>T; rs1143672:G>A; rs2257212:C>T | Missense (P409S; R509 K; L350F) | 45.4 | 40.8 | 37.9 | 24.3 | 71.5 | 29.9 | 48.4 | Decreased warfarin dose requirement | Cai et al. (2017) |
| Increased PFS of HCC patients following sorafenib therapy (OR = 0.5) | Lee et al. (2015) | ||||||||||
| SLC16A5 (MCT6) | rs4788863:C>T | Synonymous (L41L) | 26.5 | 18.7 | 31.9 | 38.0 | 65.6 | 25.8 | 25.6 | Decreased risk of cisplatin-induced ototoxicity (OR = 0.06) | Drögemöller et al. (2017) |
| SLC16A7 (MCT2) | rs3763980:G>T | Missense (T445S) | 24.7 | 23.4 | 23.0 | 13.6 | 30.7 | 22.6 | 21.5 | Increased risk of poor response to methotrexate (OR = 1.9) | Moncrieffe et al. (2010) |
| SLC19A1 (RFC) | rs1051266:G>A | Missense (R27H) | 43.2 | 45.0 | 39.9 | 43.7 | 52.9 | 40.8 | 61.8 | Decreased risk of methotrexate-induced GI toxicity (OR = 0.38) | Lima et al. (2014) |
| Increased risk of methotrexate-induced hepatotoxicity (OR = 5.3) | Suthandiram et al. (2014) | ||||||||||
| Decreased frequency of methotrexate discontinuation due to toxicity (HR = 0.33) | Bohanec Grabar et al. (2012) | ||||||||||
| Lower rapid response rate to irinotecan (OR = 3.6) | Huang et al. (2013) | ||||||||||
| rs1051296:T>G | 3′ UTR | 42.3 | 43.5 | 38.7 | 40.6 | 54.5 | 46.0 | 45.4 | Lower fraction of patients above the therapeutic threshold of methotrexate (8.6% GG vs. 40% TT; p = 0.02) | Wang et al. (2014) | |
| rs1051298:C>T | 3′ UTR | 43.6 | 45.0 | 38.3 | 45.3 | 54.3 | N/A | 51.2 | Decreased survival time following pemetrexate treatment (HR = 1.8) | Corrigan et al. (2014) | |
| SLC22A1 (OCT1) | rs12208357:C>T | Missense (R61C) | 7.7 | 5.6 | 9.5 | 2.3 | < 0.1 | 2.9 | 1 | Reduced metformin response in healthy subjects after OGTT; reduced morphine clearance and increased AUC after codeine administration; increased plasma concentrations and efficacy of tropisetron and ondansetron | Fukuda et al. (2013), Shu et al. (2007), Tzvetkov et al. (2012, 2013) |
| rs35167514:ATG>del | Missense (M420del) | 14.5 | 11.8 | 9.2 | 21.9 | < 0.1 | 11.2 | 5.5 | |||
| rs34059508:G>A | Missense (G465R) | 2.3 | 0.7 | 1.3 | 0.7 | 0 | 0.2 | 0.4 | |||
| rs34130495:G>A | Missense (G401S) | 2.6 | 1.9 | 0.7 | 0.9 | 0 | 0.3 | 0.5 | |||
| rs683369:C>G | Missense (L160F) | 22.3 | 16.4 | 16.2 | 8.7 | 14.2 | 15.4 | 3.8 | Decreased major molecular response to imatinib (OR = 0.6) | Cargnin et al. (2018) | |
| Increased risk of resistance to imatinib (OR = 1.9–3.3) | Makhtar et al. (2018) | ||||||||||
| Increased risk of imatinib-induced conjunctival hemorrhage (OR = 4.8) | Qiu et al. (2018) | ||||||||||
| 25% decreased imatinib clearance | Di Paolo et al. (2014) | ||||||||||
| rs628031:G>A | Missense (M408 V) | 41.5 | 45.4 | 35.1 | 20.2 | 27.3 | 37.7 | 27.1 | Increased risk of imatinib resistance (OR = 1.3–2.6) | Makhtar et al. (2018) | |
| Decreased major molecular response to imatinib (OR = 0.6) | Cargnin et al. (2018) | ||||||||||
| Dec. risk of metformin-induced adverse GI effects (OR = 0.39) | Tarasova et al. (2012) | ||||||||||
| SLC22A2 (OCT2) | rs316019:A>C | Missense (A270S) | 10.1 | 6 | 14.7 | 5.2 | 12.8 | 12.5 | 15.2 | Increased AUC of metformin | Song et al. (2008) |
| rs145450955:G>A | Missense (T201 M) | 0 | 0 | 0 | 0 | 0.4 | 0 | 0 | Increased AUC of metformin | Song et al. (2008) | |
| rs316019:G>T | Missense (S270A) | 10.1 | 6.0 | 14.7 | 5.2 | 12.8 | 12.5 | 15.2 | Increased Cmax and AUC of metformin | Yoon et al. (2013) | |
| Decreased risk of cisplatin-induced ototoxicity (OR = 0.12) | Lanvers-Kaminsky et al. (2015) | ||||||||||
| SLC22A4 (OCTN1) | rs1050152:C>T | Missense (L503F) | 42.2 | 31 | 41.5 | 21.7 | 0.1 | 12 | 7.2 | 30% reduced renal clearance of gapapentin | Urban et al. (2008) |
| SLC22A5 (OCTN2) | rs274558:A>G | Synonymous (L269L) | 39.1 | 50.9 | 40.1 | 31.6 | 64.4 | 62.7 | 35.8 | Increased risk of imatinib-induced edema (OR = 3.2) | Qiu et al. (2018) |
| SLC22A7 (OAT2) | rs4149178:A>G | 3’ UTR | 15.5 | 15 | 24.5 | 20.4 | 4.3 | N/A | 34.6 | Increased risk of anthracycline-induced cardiotoxicity | Visscher et al. (2015) |
| Increased risk of severe capecitabine toxicity | Pellicer et al. (2017) | ||||||||||
| SLC22A8 (OAT3) | rs11568482:A>T | Missense (I305F) | 0.0 | 0.0 | 0.0 | 0.1 | 5.9 | 0.1 | 0.1 | 50% decreased renal clearance of cefotaxime | Yee et al. (2013) |
| SLC22A16 (FLIPT2) | rs714368:A>G | Missense (H49R) | 36.9 | 22.5 | 30.4 | 41.7 | 18.1 | 21.7 | 27.5 | Increased risk of FAC-induced nausea (OR = 1.8) | Tecza et al. (2018) |
| Decreased requirement for dose delay in AC therapy | Bray et al. (2010) | ||||||||||
| rs723685:T>C | Missense (V252A) | 8.8 | 6.8 | 11.7 | 12.1 | 6.9 | 7.5 | 11.2 | Decreased requirement for dose delay in AC therapy | Bray et al. (2010) | |
| rs6907567:T>C | Synonymous (N104 N) | 21.8 | 18.2 | 30.5 | 22.5 | 41.6 | 27.6 | 36.9 | Increased hetatological toxicity of FAC (OR = 3.2) | Tecza et al. (2018) | |
| Decreased requirement for dose delay in AC therapy | Bray et al. (2010) | ||||||||||
| rs12210538:T>C | Missense (M409T) | 23.5 | 15.8 | 27.4 | 11.7 | < 0.1 | 11.3 | 3.8 | Increased requirement for dose delay in AC therapy | Bray et al. (2010) | |
| SLC28A1 (CNT1) | rs2242046:G>A | Missense (D521 N) | 50.1 | 45.2 | 55.3 | 20.8 | 7.6 | 30.3 | 8.8 | Increased risk of gemcitabine-induced hematologic toxicity | Soo et al. (2009) |
| SLC28A2 (CNT2) | rs1060896:C>A | Missense (S75R) | 65.4 | 59.2 | 58.3 | 30.2 | 8.6 | 47.8 | 17.6 | Increased OS of NSCLC patients on gemcitabine | Soo et al. (2009) |
| rs11854484:C>T | Missense (P22L) | 62.2 | 58.2 | 50.9 | 28.4 | 7.9 | 45.4 | 17.1 | Increased risk of gemcitabine-induced hematologic toxicity but increased OS of NSCLC patients | Soo et al. (2009) | |
| Increased ribavirin serum levels | Rau et al. (2013) | ||||||||||
| Increased risk of anemia in HCV patients treated with telaprevir or boceprevir (OR = 2.3) | Ampuero et al. (2015) | ||||||||||
| SLC28A3 (CNT3) | rs56350726:A>T | Missense (Y513F) | 5.9 | 12.7 | 4.9 | 2.8 | 11.5 | 7.6 | 15.4 | Higher chance of reaching sustained virological response in HCV treatment | Rau et al. (2013) |
| twofold reduced incidence of anemia in HCV patient treated with ribavirin | Doehring et al. (2011) | ||||||||||
| SLC30A8 (ZnT8) | rs16889462:G>A | Missense (R325Q) | 0.1 | 0.0 | 0.2 | 0.6 | 8.0 | 0.3 | 10.5 | Increased repaglinide efficacy | Huang et al. (2010) |
| rs13266634:C>T | Missense (R325 W) | 30.4 | 38.0 | 26.1 | 25.7 | 44.0 | 23.0 | 8.9 | Increased repaglinide efficacy | Huang et al. (2010) | |
| SLC30A9 (ZnT9) | rs1047626:G>A | Missense (M50 V) | 23.8 | 20.3 | 29.1 | 19.3 | 4.1 | 22.4 | 80.2 | Decreased risk of aspirin-exacerbated respiratory disease (OR = 0.13) | Shin et al. (2014) |
| SLC47A1 (MATE1) | rs2252281:T>C | 5′ UTR | 31.2 | 23.3 | 36.0 | 17.6 | 21.5 | N/A | 35.1 | Enhanced metformin response | Stocker et al. (2013) |
| SLC47A2 (MATE2-K) | rs12943590:G>A | 5′UTR | 27.2 | 26.7 | 34.8 | 34.5 | 46.9 | N/A | 21.5 | Decreased metformin response | Choi et al. (2011) and Stocker et al. (2013) |
MAF minor allele frequency, NFE non-Finnish Europeans, FIN Finns, ASJ Ashkenazi Jews, LAT Latinos, EAS East Asians, SAS South Asians, AFR Africans, Cmax peak serum concentration, AUC area under the concentration time curve; HCC hepatocellular carcinoma; NSCLC non-small cell lung cancer; OR odds ratio; HR hazard ratio; PFS progression-free survival; GI gastrointestinal; FAC fluorouracil, anthracycline and cyclophosphamide combination therapy; AC anthracycline and cyclophosphamide combination therapy; OS overall survival; OGTT oral glucose tolerance test