Statins are the most widely used lipid-lowering drugs across the globe for the treatment of hyperlipidemia. The cholesterol-lowering activity of statins is attributed to the inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme. This inhibition of enzyme activity increases the level of low-density lipoprotein (LDL) receptors, thereby increasing the uptake and degradation of LDL-cholesterol (LDL-C), reducing the synthesis and accumulation of cholesterol and decreasing the secretion of lipoprotein [1]. Statin therapy-induced reduction in blood concentrations of LDL-C has been shown to decrease the rates of coronary heart disease in different populations [2, 3]. This evidence is robust for both primary and secondary prevention, in men and women, in older and younger people, in people with and without diabetes mellitus, in people with and without hypertension, and in people with higher or lower levels of baseline LDL-C, with the possible exception of those with end-stage renal disease, at risk of having an atherosclerotic cardiovascular disease event [4].
Among the statins, rosuvastatin is the most potent and delivers the most significant reduction in LDL-C, with 5 mg of rosuvastatin being equivalent to up to 10 mg of atorvastatin, up to 40 mg of simvastatin, and up to 80 mg of pravastatin, respectively [5]. Apart from the potency of different statins, the ethnicity of patients, particularly Asian ancestry, has been identified as an important factor in determining statin doses [6]. Scoping review is used to chart the literature available and to identify potential research gaps. Thus, the aims of this scoping review were: (i) to identify the genetic variants associated with statin treatment responses among Asian populations, and (ii) to explore the effects of these genetic variants on drug efficacy and susceptibility to statin-induced adverse drug reactions (ADR). This review focused on pharmacogenomic studies on the four commonly prescribed statins: atorvastatin, rosuvastatin, simvastatin, and pravastatin and highlighted the research gaps that should be considered in future pharmacogenomic research.
The literature search was conducted in two databases, Medline and Embase, using free-text terms. The Boolean operator “OR” was used to group search terms into three main subjects. The first subject included terms relating to pharmacogenetics – “pharmacogen*”, or “genetic*”, or “genomic*”, or “genotype”; secondly, terms related to statins – “statins”, or “atorvastatin”, or “rosuvastatin” or “simvastatin” or “pravastatin”; and lastly terms relating to the treatment responses – “treatment response” or “efficacy” or “response”. In terms of adverse effects, the first two subjects used were similar, the subject used included the terms “adverse effect” or “adverse drug reaction”. Each of the groups of search terms was searched simultaneously with the “AND” Boolean operator to identify original research articles published up to December 2021 on pharmacogenomics of statin treatment responses, which focused on atorvastatin, rosuvastatin, simvastatin, and pravastatin. The search was limited to articles published in the English language with human subjects. Abstracts or conference proceedings were included if the content was not published before.
A total of 1907 papers from Medline and 1,382 papers from Embase were identified for treatment response to statins. After removing duplicates, 1939 original papers remained (
Articles that did not answer the research question were excluded. Articles were excluded if they contained: pharmacogenomic studies of statins other than atorvastatin, rosuvastatin, simvastatin, and pravastatin; pharmacogenomic studies with subjects of unreported ethnicities; non-pharmacogenomic studies (such as pharmacokinetic studies, gene expression studies, or cell culture studies); and population genotyping studies not involving statins. The study protocol was prospectively registered with Open Science Framework (OSF) registries (
Due to the nature of the scoping review, the quality of the individual studies was not assessed in the present study. Extracted data included information on authors, publication year, study population, statin(s) studied, gene(s) studied, study findings, and data of significant statistical value. Four reviewers (YHY, SH, NAR, and VS) independently extracted data into the data extraction form. Any conflicts were resolved within the team.
The data on (i) genetic variants studied in statin treatment response and (ii) genetic variants studied in statin-induced ADRs were summarized. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) was used as a checklist in documenting the rationale, methodology, and findings of the scoping review [7].
A total of 40 original manuscripts were included in this review: 35 articles for treatment response and 5 articles for statin-induced adverse effects.
Among the 35 papers investigating treatment response, 28 papers were studies investigating a single statin (rosuvastatin, n = 9; simvastatin, n = 10; atorvastatin, n = 8; pravastatin, n = 1), 6 papers investigated multiple statins, and 1 paper did not specify the statin(s). The parameters used to determine the treatment response in the included studies were the changes in total cholesterol (TC), triglycerides (TG), LDL-C, and high-density lipoprotein cholesterol (HDL-C) levels. The data extracted from these papers are summarized in
Genetic polymorphisms affecting pharmacokinetics of statins among Asians
SLCO1B1 | A388G rs2306283 | ATV | Indian | A: 43 |
177 DL | Greater LDL reduction (AA) | [14] |
SIM | Thai | AA: 7.7 |
391 DL | NS | [10] | ||
RSV | Chinese | AA: 6.3 |
291 DL | NS | [11] | ||
RSV, SIM | Chinese Han | AA: 4.8 |
247 CAD, HCVD | NS | [12] | ||
T521C rs4149056 | SIM | Thai | TT: 78.5 |
391 DL | NS | [10] | |
RSV | Chinese | TT: 75.4 |
291 DL | NS | [11] | ||
RSV, SIM | Chinese Han | TT: 74.7 |
247 CAD, HCVD | NS | [12] | ||
G> A rs4149081 | RSV, SIM | Chinese Han | GG: 22.7 |
247 CAD, HCVD | Greater LDL reduction (A allele) | [12] | |
C463A rs11045819 | ATV | Indian | C: 97 |
177 DL | NS | [14] | |
T89595C rs4363657 | SIM | Thai | TT: 41.2 |
391 DL | NS | [10] | |
SLC10A1 | *2 rs2296651 | RSV | Chinese | *1*1: 84.0 |
291 DL | NS | [11] |
ABCA1 | R219K | PRV | Chinese | RK: 46.6 |
365 CAD | Greater HDL increment (KK) | [26] |
ABCC2 | −24 C>T rs717620 | SIM | Chinese Han | GG: 60.7 |
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: 35 |
177 DL | Greater LDL reduction (T allele) | [14] |
C3435T rs1045642 | ATV | Indian | C: 39 |
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: 46.8 |
291 DL | Lower LDL reduction (CC) | [11] |
RSV | Chinese | CC: 50 |
386 HCVD, FH, RA | Greater LDL reduction (AA/CA) | [20] | ||
RSV | Chinese Han | CC: 51.8 |
305 DL | Greater LDL reduction (AA) | [21] | ||
G34A rs2231137 | RSV | Chinese | GG: 46.7 |
386 HCVD, FH, RA | Greater LDL reduction (GG) | [20] | |
ABCG5 | rs6720173 | ATV | Indian | C: 75 |
177 DL | NS | [14] |
ABCG8 | rs4148222 | ATV | Chinese Han | CC: 44.9 |
107 DL | Lower baseline HDL (CC) | [22] |
D18H rs11887534 | ATV | Indian | DD: 88.7 |
213 CAD; 220 H | NS | [25] | |
C1199A | ATV | Chinese Han | CC: 75.1 |
181 DL | NS | [23] | |
rs11887534, rs4148217, rs4148214, rs17606027, rs4952689, rs4953028 | ATV | Chinese Han | - | 107 DL | NS | [22] | |
Haplotypes | V | Chinese | GCGACTGCC: 34.0 |
386 DL | Greater LDL reduction (ATTATCGAC haplotype) | [24] | |
CYP2C9 | rs1934967 | V | Chinese | CC: 66.2 |
386 DL | NS | [24] |
*1 | RSV | Chinese | *1*1: 90.4 |
218 DL | Greater TC and LDL reduction (*1*3/*3*3) | [33] | |
*3 rs1057910 | RSV | Chinese | *1*1: 93.8 |
291 DL | NS | [11] | |
CYP2C19 | *2 (rs4244285; | ATV | Chinese Han | NA | 192 IS | NS | [32] |
*3 (rs4986893) | RSV | Chinese | *1*1: 37.2 |
291 DL | NS | [11] | |
rs10786172 | V | Chinese | AA: 65.9 |
386 DL | NS | [24] | |
*1 | RSV | Chinese | *1*1, *1*2, *1*3: 51 |
49 H | Greater TG reduction (poor metabolisers: *2*2/*2*3/*3*3) | [34] | |
CYP2D6 | *10(C188T) | SIM | Chinese (Ningxia Hui) | CC: 33 |
200 DL | Greater TC and LDL reduction (CC) | [35] |
*10 rs1065852 | ATV | Chinese Han | GG: 16.7 |
192 IS | Greater LDL reduction (G allele) | [32] | |
CYP3A4 | rs2242480 | ATV | Chinese Han | CC: 51.0 |
192 IS | Greater LDL reduction (C allele) | [32] |
*1G | SIM | Chinese | *1*1: 53.4 |
273 DL | NS | [30] | |
SIM, ATV | Chinese | *1*1: 49.31–52.3 |
423 DL | Greater TC reduction (*1G*1G) with ATV; NS with SIM | [31] | ||
*22 |
SIM | Chinese | No variant allele | 273 DL | NA | [30] | |
rs2740574 | ATV | Indian | A: 97 |
177 DL | Greater LDL reduction (AA) | [14] | |
rs4986910 | ATV | Indian | T: 99 |
177 DL | NS | [14] | |
CYP3A5 | *3 6986G>A |
SIM | Chinese | *1*1: 6.7 |
273 DL | NS | [30] |
ATV | Chinese | *1*1: 4.5 |
179 DL | NS | [36] | ||
ATV | Indian | A: 26 |
177 DL | NS | [14] | ||
rs4646450, rs3800959, rs776746 | ATV | Chinese Han | - | 107 DL | NS | [22] | |
CYP3AP1 | *3 |
SIM | Chinese Han | *3*3: 44.4 |
202 DL | Greater LDL reduction (*3*3 women) | [37] |
ATV | Chinese Han | *3*3: 54.8 |
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: 57.4 |
273 DL | NS | [30] |
POR | *28 | ATV | Chinese | CC: 31.8 |
179 DL | Lower mean LDL (TT) | [36] |
APOA5 | T-1131C rs662799 | V | Chinese | TT: 46.7 |
195 DL, HCVD | Greater LDL reduction (TT); |
[44] |
RSV | Chinese | TT: 47.8 |
386 DL, FH | NS | [45] | ||
APOE | E2/E3/E4 rs7412, rs429358 | RSV | Chinese | E2E2, E2E3: 8.7 |
386 DL, FH | NS | [45] |
SIM | Thai | E2E2, E2E4: 0 |
225 DL | Greater TC and LDL reduction (APOE2, APOE3 carriers) | [47] | ||
rs4420638 | RSV | Chinese | AA: 77.2 |
386 HCVD, FH, RA | Greater LDL reduction (AA/AG) | [20] | |
APOA1 | G75A | PRV | Chinese | GG: 45.8 |
97 DL | Greater TC and LDL reduction (AA/GA) | [48] |
HMGCR | rs3931914 | V | Chinese | GG: 47.4 |
386 DL | NS | [24] |
rs12916 | V | Chinese | CC: 30.1 |
386 DL | Greater LDL reduction (CT/TT) | [24] | |
Haplotypes | V | Chinese | GCGTTCA: 44.2 |
386 DL | Higher LDL (CCGTCCA haplotype) | [24] | |
rs3846662 | ATV | Korean | GG: 54.2 |
24 H | Higher LDL (GG) | [50] | |
LDLR | rs1433099 | RSV | Chinese | CC: 52.5 |
386 HCVD, FH, RA | Greater LDL reduction (CC/CT) | [20] |
PCSK9 | I474V |
SIM | Thai | II: 96.4 |
225 DL | Greater LDL reduction (IV) | [47] |
R46L rs11591147; |
SIM | Thai | NA | 225 DL | NA | [47] | |
SREBF1 | rs9902941 | V | Chinese | CC: 84.4 |
386 DL | Greater LDL reduction (CT/TT) | [24] |
CYP7A1 | A-204C rs3808607 | ATV | Indian | A: 59 |
177 DL | Greater LDL reduction (AA) | [14] |
ATV | Chinese Han | GG: 34.6 |
107 DL | NS | [22] | ||
ATV | Chinese Han | AA: 30.4 |
181 DL | Greater TG reduction (AA) | [23] | ||
rs4738687 | V | Chinese | TT: 42.4 |
386 DL | NS | [24] | |
rs2162459 | V | Chinese | GG: 31.8 |
386 DL | NS | [24] | |
ATV | Chinese Han | GG: 23.4 |
107 DL | NS | [22] | ||
rs8192870 | ATV | Chinese Han | TT: 51.4 |
107 DL | Greater LDL reduction (TT) | [22] | |
rs1457042, rs6997473, rs11786580, rs8192879 | ATV | Chinese Han | - | 107 DL | NS | [22] | |
rs3824260 | SIM | Chinese Han | GG: 37.5 |
420 DL | Lower LDL reduction (AA) |
[53] | |
CETP | TaqIB | SIM | Thai | B1B1:4 |
225 DL | Greater TC and LDL reduction (B1 carriers) | [47] |
LPL | C1421G | RSV | Chinese | CC: 76.7 |
386 HCVD, FH, RA | Greater LDL reduction (CG/GG) | [20] |
LCAT | rs255052 | RSV | Chinese | GG: 82.9 |
386 HCVD, FH, RA | Greater LDL reduction (GG) | [20] |
MMP9 | C1562T rs3918242 | SIM | Chinese | CC: 71.3 |
264 CAD | Greater LDL reduction (TT) | [71] |
EL | 2037T/C rs3744843 | RSV | Chinese | TT: 56.2 |
121 CAD | NS | [76] |
2237 G/A rs3744841 | RSV | Chinese | GG: 38.0 |
121 CAD | NS | [76] | |
FMO3 | Val257Met | RSV | Chinese | GG: 59.5 |
386 HCVD, FH, RA | Greater LDL reduction (GG) | [20] |
PON1 | Q192R | SIM | Chinese | QQ: 23.7 |
236 CAD | Greater HDL increment (RR) | [64] |
TIMD4-HAVCR1 | rs1501908 | ATV | Chinese Han | CC: 51.0 |
724 H, CAD, IS | Lower TC and LDL level (G allele) | [69] |
rs12522248 | ATV | Chinese Han | TT: 70.4 |
724 H, CAD, IS | Lower TC and LDL level (C allele) | [69] | |
rs2036402 | ATV | Chinese Han | TT: 79.3 |
724 H, CAD, IS | Lower TC and LDL level (TC) | [69] | |
LEP | G2548A | SIM | Chinese | AA: 40.1 |
212 DL | NS | [61] |
LEPR | Q223R | SIM | Chinese | RR: 78.3 |
212 DL | Greater TC and TC reduction (RR) | [61] |
A223G | SIM | Chinese | GG: 74.0 |
312 CAD | Lower HDL increment (AA) | [62] | |
FXR | G-1T |
RSV | Chinese | GG: 81.6 |
385 DL | Greater TC and LDL reduction (T allele) | [66] |
SCAP | A2386G | RSV | Indian | AA: 36.6 |
63 DL | Greater TC and LDL reduction (G allele) | [67] |
TNF-α | C-857T | U | Japanese | CC: 71.7 |
322 T2DM | Higher LDL and resistant to statin (T allele) | [70] |
NCAN/CILP2/PBX4 | rs16996148 | RSV | Chinese | GG: 81.5 |
386 HCVD, FH, RA | Greater LDL reduction (GG) | [20] |
Drugs studied: ATV, atorvastatin; PRV, pravastatin; RSV, rosuvastatin; SIM, simvastatin; V, various statins; U, unknown statins
Conference paper
Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol TG, triglycerides; NS, not significant; DL, dyslipidemic patients; HCVD, high-risk cardiovascular disease population; FH, familial hypercholesterolemia; RA, rheumatoid arthritis; CAD, coronary artery disease; IS, ischemic stroke; T2DM, Type 2 diabetes mellitus; H, healthy; NA, not available
Transporters are membrane proteins present in cells to regulate the influx of essential nutrients and ions and the efflux of cellular waste and xenobiotics, such as toxins and drugs. The two major superfamilies of transporters that play an essential role in drug disposition are solute carrier (SLC) and ATP-binding cassette (ABC) transporters.
Statins are transported into the liver by the organic anion transporting polypeptide 1B1 (OATP1B1) encoded by
Multidrug resistance-associated protein 2 (MRP2) also known as ABC sub-family C member 2 (ABCC2) encoded by the
The
The
The protein encoded by
The
Genetic polymorphisms in cytochrome P450 (CYP) genes have been associated with the efficacy of selected statins by influencing their hepatic metabolism. The CYP450 enzymes catalyze the metabolism of most statins, except pravastatin and rosuvastatin (
Hu et al. [30] found no significant association between
Studies found no significant associations between statins response in LDL-C reduction and
Li et al. [35] investigated the effects of the lipid-lowering effect of simvastatin and
CYP3A5 is another CYP3A family enzyme that is involved in metabolism of simvastatin and atorvastatin. However, no studies found any significant associations between
P450 oxidoreductase (POR) plays an essential role for CYP450 activity by transferring electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to CYP3A enzymes, which metabolize various statins, including atorvastatin [38]. Wei and Zhang [36] investigated the association of
Apolipoproteins have a role in regulating lipoprotein metabolism [39]. Polymorphisms in several apolipoproteins, such as
Apolipoprotein E (APOE) is expressed in the brain and the liver and is a ligand for the LDL receptor (LDLR) [46]. Similar to
Liu et al. [48] found that there was a significant reduction in TC, LDL-C, and APOB levels after 12 weeks of pravastatin therapy only among Chinese hyperlipidemia patients expressing the
3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) is the rate-controlling enzyme for cholesterol synthesis via the mevalonate pathway, which is the target enzyme of statins [49].
Chien et al. [24] explored the association of two
Hu et al. [20] reported that
In addition to LDL receptors, proprotein convertase subtilisin/kexin type 9 (
Sterol regulatory element-binding transcription factor 1 (SREBF1) is the transcription factor that regulates the expression of hepatic LDLR [24]. A study explored the association of
Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in bile acid production, which is essential for cholesterol elimination from the body. Hence, genetic variants in the gene may indirectly affect an individual's sensitivity to the lipid-lowering effects of statins [52]. Among the Chinese Han hypercholesterolemia patients whose LDL levels were recorded in pursuance of atorvastatin treatment, a significantly greater reduction was, among all the 7 variants studied, demonstrated only for rs8192870*T homozygotes [22]. A similar effect was also seen with Indian and Chinese patients treated with atorvastatin who were homozygous for the rs3808607*A allele [14, 23]. However, the study by Chien et al. [24] did not find any associations with the two SNPs, rs4738687 and rs2162459, in their cohort of Chinese patients. Recently, Liu et al. [53] reported that
Cholesterol ester transfer protein (CETP) encoded by the
Lipoprotein Lipase (LPL) plays a role in lipid metabolism by catalyzing the hydrolysis of triacylglycerol in chylomicrons and very low-density lipoproteins (VLDL) for tissue utilization [57]. Hu et al. [20] reported that Chinese patients with the C1421G CC genotype demonstrated a significantly lower reduction in LDL-C levels compared to those with the CG or GG genotypes in response to rosuvastatin treatment.
Lecithin-cholesterol acyltransferase (LCAT) plays a key role in cholesterol transport and removal by catalyzing the conversion of cholesterol and lecithin to cholesteryl esters and lysophosphatidylcholines on the surface of HDLs, which is a crucial step in the maturation of HDLs [58]. A study investigated the association of
In addition to the aforementioned gene variations affecting pharmacokinetics and pharmacodynamics of statins, other gene polymorphisms were also studied among Asian populations. Flavin-containing monooxygenase 3 (FMO3) catalyzes the oxygenation of various compounds and plays a regulatory role in cholesterol metabolism [59]. A study revealed that the
Leptin may also be involved in regulating cholesterol metabolism via other mechanisms, such as downregulating activity of HMG-CoA reductase and upregulating activity of sterol and cholesterol hydroxylases to decease VLDL levels [60]. Li et al. [61] investigated the association between
Paraoxonase 1 (PON1) is an HDL-associated enzyme involved in reducing lipid peroxide accumulation on LDL, suggestive of a protective role against cardiovascular disease [63]. Fu et al. [64] noticed that there was significant association between plasma HDL-C changes with
Farnesoid X receptor (FXR), the bile acid-activated nuclear receptor with an essential role in lipid and carbohydrate metabolism, is a regulator of drug transporters involved in statin disposition, including SLCO1B1 [65]. A study investigated the impact of
T-cell immunoglobulin and mucin domain 4 gene (
Matrix metalloproteinase 9 (MMP9) has been shown to be associated in the pathogenesis and progression of cardiovascular diseases [71]. Xu et al. [71] investigated the association of
Endothelial lipase (EL) has a role in modulating lipid metabolism by lowering HDL-C levels [75]. However, Cai et al. [76] reported that there was no significant effect of
Five papers investigated associations between various genetic variants with statin-induced ADRs, studying the effects of either just one statin [33, 77] or multiple statins [78,79,80] (
Genetic polymorphisms related to susceptibility to statin-induced adverse drug reactions among Asians
SLCO1B1 | T521C (rs4149056) | V | Chinese | TT: 68.2 |
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: 78.8 |
52 SRM | NS | [78] | ||
A388G (rs2306283) | V | Chinese | AA: 6.8 |
148 CAD | NS | [79] | |
APOE | C526T (rs7412) | V | Chinese | CC: 87.2 |
148 CAD | NS | [79] |
T388C (rs429358) | V | Chinese | TT: 16.2 |
148 CAD | NS | [79] | |
CYP2D6 | *1 | RSV | Chinese | NA | 16 DL | NS | [33] |
CYP3A5 | A6986G (rs776746) | V | Chinese | AA: 5.4 |
148 CAD | NS | [79] |
LEP | G2548A | SIM | Chinese | AA: 53.0 |
587 DL | CK elevation (AA) | [77] |
LEPR | Q223R | SIM | Chinese | RR: 77.2 |
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: 98.1 |
52 SRM | NS | [78] |
GATM | rs9806699 | V | Japanese | AA: 78.6 |
52 SRM | NS | [78] |
Drugs studied: ATV, atorvastatin; RSV, rosuvastatin; SIM, simvastatin; V, various statins
NS, not significant; DL, dyslipidemic patients; CAD, coronary artery disease; H, healthy; NA, not available; CK, creatine kinase; SRM, statin-related myopathy
Sai et al. [78] compared genetic variants in three candidate genes (
The study with the largest cohort classified statin-induced myopathy based on CK levels and geographic location in China (392 patients from Dongzhi and 195 patients from Beijing) over two time points, specifically after 4 weeks’ and 8 weeks’ treatment with simvastatin [77]. Jiang et al. [77] only found significant elevation of CK levels among patients in Dongzhi with either the AA genotype in the
On the other hand, Liu et al. [79] reported that the risk for myotoxicity was significantly higher among patients who were C allele carriers of
Although statins are generally effective and well-tolerated, there are interindividual differences that contribute to decreased efficacy and an increase in susceptibility to adverse effects. Ethnicity of patients is one of the factors that affect the efficacy and toxicity of statin therapy, and it has become an integral component of pharmacogenomics studies [82]. A meta-analysis of population-scale sequencing projects revealed that there are inter-ethnic differences in CYP450 polymorphisms between populations, which are crucial for personalized drug therapy and healthcare programs [29].
Asia is the largest and most diverse continent with several heterogenous populations with significant implications for pharmacogenomics. Malaysia and Singapore are countries with multiple ethnicities, predominantly Malay, Chinese, and Indian. These countries provide noticeable examples of pharmacogenomic diversity across different ethnicities within the population. Ho et al. [83] reported that there were significant inter-ethnic differences in allele frequencies across
Several candidate genes have been studied to investigate their effects on efficacy and safety of statins among Asian populations, including transmembrane transporters, CYP450 isoenzymes, and apolipoproteins.
Several clinical trials investigating the statin treatment response in Western population had underrepresentation of patients of Asian ethnicities. In this review, most of the studies have been conducted among Chinese patients and to a lesser extent among Indian, Thai, and Japanese patients. There are limited large-scale pharmacogenetic studies conducted among patients of non-Caucasian ethnicities to explore the effect of ethnicity on the efficacy and susceptibility of adverse effects to statin treatment. The US Food and Drug Administration (FDA) [89] recommends dosage reduction of rosuvastatin in Asian patients stating in their warning that Asian patients are at higher risk for rhabdomyolysis. The FDA has advised that rosuvastatin dose should be halved in Asian patients because of the 2-fold increase in rosuvastatin exposure when compared to Caucasian patients [89]. Nevertheless, a recent study that evaluated the effect of
This review has identified a gap in our current knowledge in understanding the underlying genetic basis of variability in statin response and predisposition to adverse effects in the many ethnic groups in Asia. Conflicting findings from various studies among Chinese patients have also been reported. This discrepancy could be attributed to other non-genetic confounding factors, such as age, gender, body mass index, diet, concomitant medications, lifestyle and environmental factors that could also influence efficacy, and risk of ADRs of statins [91]. These factors should be considered in study design. In addition, most studies have investigated a small number of genetic variants. However, this scoping review did not analyze the quality of included studies. This scoping review only focused on original research articles published in English articles, and therefore it is possible that some relevant studies published in other languages could have been missed and not included in this study.
Pharmacogenetic or pharmacogenomic studies provide a fundamental approach toward personalized medicine in statin treatment outcomes by exploring the individual variability in response to statin treatment. Although statins are generally effective and well-tolerated, there are interindividual differences that contribute to a decreased efficacy and an increased risk of adverse effects to statin therapy. However, various confounding factors should be considered in study design to explore the true effect of ethnicity on statin treatment outcomes. Due to paucity of studies on patients of various Asian ethnicities and discrepancies in the findings from various published papers, continued research pertaining to ethnicity, the candidate genes, and their association with statin efficacy and risk of ADRs is needed to underpin the potential value of personalized medicine in statin therapy.