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Pharmacogenomics of response to statin treatment and susceptibility to statin-induced adverse drug reactions in Asians: a scoping review

Hui-Yin Yow

Hui-Yin Yow

  • Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti MalayaKuala Lumpur, Malaysia
  • School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's UniversityMalaysia
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Yow, Hui-Yin
, 
Sharina Hamzah

Sharina Hamzah

  • School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's UniversityMalaysia
  • Medical Advancement for Better Quality of Life Impact Lab, Taylor's UniversityMalaysia
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Hamzah, Sharina
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Nusaibah Abdul Rahim

Nusaibah Abdul Rahim

Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti MalayaKuala Lumpur, Malaysia
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Abdul Rahim, Nusaibah
 y 
Vijayaprakash Suppiah

Vijayaprakash Suppiah

  • Clinical and Health Sciences, University of South AustraliaAdelaide, Australia
  • Australian Centre for Precision Health, University of South AustraliaAdelaide, Australia
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Suppiah, Vijayaprakash
  
09 oct 2023
Pharmacogenomics of response to statin treatment and susceptibility to statin-induced adverse drug reactions in Asians: a scoping review's Cover Image
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Categoría del artículo: Review
Publicado en línea: 09 oct 2023
Páginas: 95 - 114
DOI: https://doi.org/10.2478/abm-2023-0050
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© 2023 Hui-Yin Yow et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1.

Flow diagram of selection process for scoping review of pharmacogenomics of statin treatment outcomes in Asians based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Flow diagram of selection process for scoping review of pharmacogenomics of statin treatment outcomes in Asians based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 2.

Gene polymorphisms significantly affecting the therapeutic response of statins (atorvastatin, rosuvastatin, simvastatin, and pravastatin) in Asian populations. Statins are transported into hepatocytes via active transport through SLC transporters and metabolized mainly by CYP enzymes and eliminated by efflux pumps, ABC proteins. In terms of mechanism of action, statins inhibit HMGCR, which is the step-limiting step in cholesterol synthesis. Created with BioRender.com. Adapted from PharmGKB [8].ABC, ATP-binding cassette; APO, apolipoprotein; APOA5, Apolipoprotein A-V; APOE, apolipoprotein E; CETP, cholesterol ester transfer protein; CYP, cytochrome P450; CYP7A1, cholesterol 7-α-hydroxylase; HDL, high-density lipoprotein; HMGCR, HMG-CoA reductase; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; SLC, solute carrier; VLDL, very-low-density lipoprotein.
Gene polymorphisms significantly affecting the therapeutic response of statins (atorvastatin, rosuvastatin, simvastatin, and pravastatin) in Asian populations. Statins are transported into hepatocytes via active transport through SLC transporters and metabolized mainly by CYP enzymes and eliminated by efflux pumps, ABC proteins. In terms of mechanism of action, statins inhibit HMGCR, which is the step-limiting step in cholesterol synthesis. Created with BioRender.com. Adapted from PharmGKB [8].ABC, ATP-binding cassette; APO, apolipoprotein; APOA5, Apolipoprotein A-V; APOE, apolipoprotein E; CETP, cholesterol ester transfer protein; CYP, cytochrome P450; CYP7A1, cholesterol 7-α-hydroxylase; HDL, high-density lipoprotein; HMGCR, HMG-CoA reductase; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase; SLC, solute carrier; VLDL, very-low-density lipoprotein.

Genetic polymorphisms related to susceptibility to statin-induced adverse drug reactions among Asians

Gene Variant Statin* Ethnicity Allele/Genotype/Haplotype frequency (%) Study population Adverse drug reaction Reference
SLCO1B1 T521C (rs4149056) V Chinese TT: 68.2TC, CC: 31.8 148 CAD Higher risk for myopathy (TC/CC treated with RSV); NS for ATV and SIM [79]
V Chinese (Hakka) NA 47 H NS [80]
V Japanese TT: 78.8TC, CC: 21.2 52 SRM NS [78]
A388G (rs2306283) V Chinese AA: 6.8GA: 31.1GG: 62.2 148 CAD NS [79]
APOE C526T (rs7412) V Chinese CC: 87.2TC, TT: 12.8 148 CAD NS [79]
T388C (rs429358) V Chinese TT: 16.2TC, CC: 83.8 148 CAD NS [79]
CYP2D6 *1 RSV Chinese NA 16 DL NS [33]
CYP3A5 A6986G (rs776746) V Chinese AA: 5.4GA: 42.6 148 CAD NS [79]
LEP G2548A SIM Chinese AA: 53.0GA:40.9GG: 6.1 587 DL CK elevation (AA) [77]
LEPR Q223R SIM Chinese RR: 77.2RQ:21.6QQ: 1.2 587 DL CK elevation (RQ/QQ) [77]
HLA-DRB1 *04:06 V Japanese Carrier: 17.3 52 SRM Higher risk for myopathy [78]
RYR2 rs2819742 V Japanese TT: 98.1TC, CC: 1.9 52 SRM NS [78]
GATM rs9806699 V Japanese AA: 78.6GA, GG: 21.4 52 SRM NS [78]

Genetic polymorphisms affecting pharmacokinetics of statins among Asians

Gene Variant Statin* Ethnic Allele/Genotype/Haplotype frequency (%) Study population Effect Ref.
Transporter
SLCO1B1 A388G rs2306283 ATV Indian A: 43G: 57 177 DL Greater LDL reduction (AA) [14]
SIM Thai AA: 7.7AG: 34.8GG: 57.5 391 DL NS [10]
RSV Chinese AA: 6.3AG: 35.8GG: 57.9 291 DL NS [11]
RSV, SIM Chinese Han AA: 4.8AG: 35.1GG: 60.1 247 CAD, HCVD NS [12]
T521C rs4149056 SIM Thai TT: 78.5TC: 19.4CC: 2.1 391 DL NS [10]
RSV Chinese TT: 75.4TC: 22.8CC: 1.8 291 DL NS [11]
RSV, SIM Chinese Han TT: 74.7TC: 23.3CC: 2.0 247 CAD, HCVD NS [12]
G> A rs4149081 RSV, SIM Chinese Han GG: 22.7GA: 53.4AA: 23.9 247 CAD, HCVD Greater LDL reduction (A allele) [12]
C463A rs11045819 ATV Indian C: 97A: 3 177 DL NS [14]
T89595C rs4363657 SIM Thai TT: 41.2TC: 43.2CC: 15.6 391 DL NS [10]
SLC10A1 *2 rs2296651 RSV Chinese *1*1: 84.0*1*2: 14.9*2*2: 1.1 291 DL NS [11]
ABCA1 R219K PRV Chinese RK: 46.6RR: 38.3KK: 15.1 365 CAD Greater HDL increment (KK) [26]
ABCC2 −24 C>T rs717620 SIM Chinese Han GG: 60.7GA: 31.4AA: 7.9 318 DL Low response of HDL elevation (A allele) [17]
ATV Chinese Han NA 318 HCVD Significant different in percentage of LDL change [18]#
ABCB1 G2677T rs2032582 ATV Indian G: 35T: 65 177 DL Greater LDL reduction (T allele) [14]
C3435T rs1045642 ATV Indian C: 39T: 61 177 DL Greater LDL reduction (T allele) [14]
rs2235013, rs2235033, rs1128503, rs10276036 ATV Chinese Han NA 318 HCVD Significant different in percentage of LDL change [18]#
ABCG2 C421A rs2231142 RSV Chinese CC: 46.8CA: 39.1AA: 14.1 291 DL Lower LDL reduction (CC) [11]
RSV Chinese CC: 50CA: 35.7AA: 14.3 386 HCVD, FH, RA Greater LDL reduction (AA/CA) [20]
RSV Chinese Han CC: 51.8CA: 35.4AA: 12.8 305 DL Greater LDL reduction (AA) [21]
G34A rs2231137 RSV Chinese GG: 46.7GA: 43.2AA: 10.1 386 HCVD, FH, RA Greater LDL reduction (GG) [20]
ABCG5 rs6720173 ATV Indian C: 75G: 25 177 DL NS [14]
ABCG8 rs4148222 ATV Chinese Han CC: 44.9CT: 43TT: 12.1 107 DL Lower baseline HDL (CC) [22]
D18H rs11887534 ATV Indian DD: 88.7DH, HH: 11.3 213 CAD; 220 H NS [25]
C1199A ATV Chinese Han CC: 75.1CA, AA: 24.9 181 DL NS [23]
rs11887534, rs4148217, rs4148214, rs17606027, rs4952689, rs4953028 ATV Chinese Han - 107 DL NS [22]
Haplotypes V Chinese GCGACTGCC: 34.0GCGATCGCC: 28.3GCGATTGCC: 8.9ATTATCGAC: 5.3 386 DL Greater LDL reduction (ATTATCGAC haplotype) [24]
Cytochrome P450 and related enzymes
CYP2C9 rs1934967 V Chinese CC: 66.2CT: 30.1TT: 3.7 386 DL NS [24]
*1 RSV Chinese *1*1: 90.4*1*3, *3*3: 9.6 218 DL Greater TC and LDL reduction (*1*3/*3*3) [33]
*3 rs1057910 RSV Chinese *1*1: 93.8*1*3: 5.8*3*3: 0.4 291 DL NS [11]
CYP2C19 *2 (rs4244285; ATV Chinese Han NA 192 IS NS [32]
*3 (rs4986893) RSV Chinese *1*1: 37.2*1*2, *1*3: 54.4*2*2, *2*3: 8.4 291 DL NS [11]
rs10786172 V Chinese AA: 65.9AG: 30.2GG: 3.9 386 DL NS [24]
*1 RSV Chinese *1*1, *1*2, *1*3: 51*2*2, *2*3, *3*3: 49 49 H Greater TG reduction (poor metabolisers: *2*2/*2*3/*3*3) [34]
CYP2D6 *10(C188T) SIM Chinese (Ningxia Hui) CC: 33CT: 39TT: 28 200 DL Greater TC and LDL reduction (CC) [35]
*10 rs1065852 ATV Chinese Han GG: 16.7GA: 49.5AA: 33.8 192 IS Greater LDL reduction (G allele) [32]
CYP3A4 rs2242480 ATV Chinese Han CC: 51.0CT: 44.3TT: 4.7 192 IS Greater LDL reduction (C allele) [32]
*1G SIM Chinese *1*1: 53.4*1*1G: 39.9*1G*1G: 6.7 273 DL NS [30]
SIM, ATV Chinese *1*1: 49.31–52.3*1*1G: 40.70–45.6*1G*1G: 5.07–7.1 423 DL Greater TC reduction (*1G*1G) with ATV; NS with SIM [31]
*22rs35599367 SIM Chinese No variant allele 273 DL NA [30]
rs2740574 ATV Indian A: 97G: 3 177 DL Greater LDL reduction (AA) [14]
rs4986910 ATV Indian T: 99C: 1 177 DL NS [14]
CYP3A5 *3 6986G>Ars776746 SIM Chinese *1*1: 6.7*1*3: 39.8*3*3: 53.5 273 DL NS [30]
ATV Chinese *1*1: 4.5*1*3: 43.5*3*3: 52.0 179 DL NS [36]
ATV Indian A: 26G: 74 177 DL NS [14]
rs4646450, rs3800959, rs776746 ATV Chinese Han - 107 DL NS [22]
CYP3AP1 *3-44G>Ars217718 SIM Chinese Han *3*3: 44.4*1*3: 46.0*1*1: 9.6 202 DL Greater LDL reduction (*3*3 women) [37]
ATV Chinese Han *3*3: 54.8*1*3: 41.8*1*1: 3.4 177 DL Greater TC reduction (*3*3 women) [37]
CYP4F2 rs2108622 ATV Chinese Han NA 192 IS NS [32]
PPARA A>G rs4823613 SIM Chinese AA: 57.4AG: 37.4GG: 5.2 273 DL NS [30]
POR *28 ATV Chinese CC: 31.8CT: 53.1TT: 15.1 179 DL Lower mean LDL (TT) [36]
Apolipoproteins
APOA5 T-1131C rs662799 V Chinese TT: 46.7TC: 46.7CC: 6.6 195 DL, HCVD Greater LDL reduction (TT);Greater HDL and TG reduction (TT; only ATV & SIM) [44]
RSV Chinese TT: 47.8TC: 41.3CC: 10.9 386 DL, FH NS [45]
APOE E2/E3/E4 rs7412, rs429358 RSV Chinese E2E2, E2E3: 8.7E3E3: 69.0E4E4, E4E3: 22.3 386 DL, FH NS [45]
SIM Thai E2E2, E2E4: 0E2E3: 14.22E3E3: 62.22E3E4: 20.44E4E4: 3.11 225 DL Greater TC and LDL reduction (APOE2, APOE3 carriers) [47]
rs4420638 RSV Chinese AA: 77.2AG: 20.7GG: 2.1 386 HCVD, FH, RA Greater LDL reduction (AA/AG) [20]
APOA1 G75A PRV Chinese GG: 45.8AA: 14.5GA: 39.7 97 DL Greater TC and LDL reduction (AA/GA) [48]
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase
HMGCR rs3931914 V Chinese GG: 47.4GC: 42.5CC: 10.1 386 DL NS [24]
rs12916 V Chinese CC: 30.1CT: 50.9TT: 19.0 386 DL Greater LDL reduction (CT/TT) [24]
Haplotypes V Chinese GCGTTCA: 44.2CCGTCCA: 23.5GTGACTA: 19.1CCATCCA: 7.4 386 DL Higher LDL (CCGTCCA haplotype) [24]
rs3846662 ATV Korean GG: 54.2AA: 45.8 24 H Higher LDL (GG) [50]
LDL receptor and related genes
LDLR rs1433099 RSV Chinese CC: 52.5CT: 40.0TT: 7.5 386 HCVD, FH, RA Greater LDL reduction (CC/CT) [20]
PCSK9 I474Vrs562556 SIM Thai II: 96.4IV: 3.6VV: 0 225 DL Greater LDL reduction (IV) [47]
R46L rs11591147;E670G rs505151 SIM Thai NA 225 DL NA [47]
SREBF1 rs9902941 V Chinese CC: 84.4CT: 15.1TT: 0.5 386 DL Greater LDL reduction (CT/TT) [24]
Enzymes involved in cholesterol elimination and reverse cholesterol transport
CYP7A1 A-204C rs3808607 ATV Indian A: 59C: 41 177 DL Greater LDL reduction (AA) [14]
ATV Chinese Han GG: 34.6GT: 50.5TT: 15.0 107 DL NS [22]
ATV Chinese Han AA: 30.4AC: 47.0CC: 22.6 181 DL Greater TG reduction (AA) [23]
rs4738687 V Chinese TT: 42.4TC: 42.1CC: 15.5 386 DL NS [24]
rs2162459 V Chinese GG: 31.8GA: 49.9AA: 18.3 386 DL NS [24]
ATV Chinese Han GG: 23.4GA: 54.2AA: 22.4 107 DL NS [22]
rs8192870 ATV Chinese Han TT: 51.4TG: 44.9GG: 3.7 107 DL Greater LDL reduction (TT) [22]
rs1457042, rs6997473, rs11786580, rs8192879 ATV Chinese Han - 107 DL NS [22]
rs3824260 SIM Chinese Han GG: 37.5GA: 44.3AA: 18.2 420 DL Lower LDL reduction (AA)Higher HDL reduction (GG) [53]
CETP TaqIB SIM Thai B1B1:4B1B2: 83.6B2B2: 12.4 225 DL Greater TC and LDL reduction (B1 carriers) [47]
LPL C1421G RSV Chinese CC: 76.7CG: 22.2GG: 1.1 386 HCVD, FH, RA Greater LDL reduction (CG/GG) [20]
LCAT rs255052 RSV Chinese GG: 82.9GA: 16.6AA: 0.5 386 HCVD, FH, RA Greater LDL reduction (GG) [20]
Other genes
MMP9 C1562T rs3918242 SIM Chinese CC: 71.3CT: 26.0TT: 2.7 264 CAD Greater LDL reduction (TT) [71]
EL 2037T/C rs3744843 RSV Chinese TT: 56.2CT: 38.8CC: 5.0 121 CAD NS [76]
2237 G/A rs3744841 RSV Chinese GG: 38.0GA: 49.6AA: 12.4 121 CAD NS [76]
FMO3 Val257Met RSV Chinese GG: 59.5GA: 34.5AA: 6.0 386 HCVD, FH, RA Greater LDL reduction (GG) [20]
PON1 Q192R SIM Chinese QQ: 23.7QR: 53.4RR: 22.9 236 CAD Greater HDL increment (RR) [64]
TIMD4-HAVCR1 rs1501908 ATV Chinese Han CC: 51.0CG: 40.1GG: 8.9 724 H, CAD, IS Lower TC and LDL level (G allele) [69]
rs12522248 ATV Chinese Han TT: 70.4TC: 26.2CC: 3.4 724 H, CAD, IS Lower TC and LDL level (C allele) [69]
rs2036402 ATV Chinese Han TT: 79.3TC: 19.5CC: 1.2 724 H, CAD, IS Lower TC and LDL level (TC) [69]
LEP G2548A SIM Chinese AA: 40.1GA: 54.2GG: 5.7 212 DL NS [61]
LEPR Q223R SIM Chinese RR: 78.3QR: 21.7QQ: 0% 212 DL Greater TC and TC reduction (RR) [61]
A223G SIM Chinese GG: 74.0AG: 23.4AA: 2.6 312 CAD Lower HDL increment (AA) [62]
FXR G-1Trs56163822 RSV Chinese GG: 81.6GT: 17.7TT: 0.7 385 DL Greater TC and LDL reduction (T allele) [66]
SCAP A2386G RSV Indian AA: 36.6AG: 31.7GG:31.7 63 DL Greater TC and LDL reduction (G allele) [67]
TNF-α C-857T U Japanese CC: 71.7CT, TT: 28.3 322 T2DM Higher LDL and resistant to statin (T allele) [70]
NCAN/CILP2/PBX4 rs16996148 RSV Chinese GG: 81.5GT: 18.5 386 HCVD, FH, RA Greater LDL reduction (GG) [20]
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