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

Yow, Hui-Yin; Hamzah, Sharina; Abdul Rahim, Nusaibah; Suppiah, Vijayaprakash

doi:10.2478/abm-2023-0050

Figures & Tables

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).

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]
APOE	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]
ABCC2	−24 C>T rs717620	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]
CYP2D6	^*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]
	^*1G	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]
CYP3AP1	^*3-44G>Ars217718	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]
APOA5	T-1131C rs662799	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]
	E2/E3/E4 rs7412, rs429358	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]
PCSK9	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]
	rs2162459	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]
EL	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]
LEPR	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]

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

Figures & Tables

Figure 1.

Figure 2.

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

Genetic polymorphisms affecting pharmacokinetics of statins among Asians

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