Genetic Variability of SLCO1B3 and Its Influence on Lipid Levels and Statin Efficacy in Han and Uighur Populations

doi:10.21203/rs.3.rs-3310639/v1

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Genetic Variability of SLCO1B3 and Its Influence on Lipid Levels and Statin Efficacy in Han and Uighur Populations

https://doi.org/10.21203/rs.3.rs-3310639/v1

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Background

Lowering plasma LDL cholesterol levels reduces the risk of atherosclerotic cardiovascular disease (ASCVD). Genetic factors, including single nucleotide polymorphisms (SNPs), affect lipid abnormalities. Statins are the main treatment for lipid disorders, but their effectiveness is influenced by genetics.

Objective

This study examines the impact of SLCO1B3 genetic variability on lipid levels and statin efficacy, particularly on statin sensitivity.

Methods

780 coronary atherosclerotic heart disease patients on oral statins for ≥ 4 weeks were studied. Clinical data and SNP genotyping were collected.

Results

Statin therapy effectively reduces TC, TG, LDL-C, APOA1, and APOB in Han and Uighur populations, with limited impact on HDL-C and Lpa. In the Han population, rs2117032 significantly affects APOB levels, post-statin APOB, Lpa, AST levels, and rate of LDL-C reduction. In Uighurs, rs2117032 significantly affects Tbil levels. In Han individuals, rs3764006 significantly influences TBil, ALT levels, post-statin LDL-C, APOB, Lpa, AST levels, and rates of LDL-C and APOB reduction, correlating with statin sensitivity. In Uighurs, rs3764006 notably affects APOA1 levels. For Han population, rs4149117 significantly impacts LDL-C, TC, TG levels, post-statin TG, ALT, AST levels, and LDL-C reduction. In Uighurs, rs4149117 affects post-statin AST and correlates with statin sensitivity. Additionally, rs2417940 significantly affects Tbil, post-statin TG, and rate of LDL-C reduction in Han, and such effects in Uighurs. In Han population, H3 (C-G-G) haplotype frequencies are higher in statin-sensitive individuals (OR = 1.861, 95% CI: 1.178–2.939, p = 0.007). In Uighurs, H6 (T-A-T) haplotype frequencies are higher in statin-sensitive subjects (OR = 4.906, 95% CI: 1.549–15.541, p = 0.0029).

Conclusion

SLCO1B3

Statin

lipid

polymorphisms

rs2117032

rs3764006

rs4149117

rs2417940

Cardiovascular disease (CVD) stands as a predominant cause of human mortality, imposing substantial health and economic burdens upon populations worldwide(1).Dyslipidemia emerges as a crucial risk factor for cardiovascular disease, with global burdens of dyslipidemia experiencing a substantial surge over the past three decades, in terms of both morbidity and associated mortality rates. Among these, hypercholesterolemia takes precedence as the most prevalent manifestation. Notably, elevated levels of plasma low-density lipoprotein cholesterol (LDL-C) are deemed a primary contributor to the development of atherosclerotic cardiovascular disease (ASCVD) in both developed nations and developing economies alike(2–4).Genetic factors, encompassing single nucleotide polymorphisms (SNPs) among them, stand as the principal risk elements underlying the occurrence of lipid abnormalities(5–7).

The demonstrated reduction of plasma LDL cholesterol levels has substantiated its capacity to mitigate the risk of atherosclerotic cardiovascular disease (ASCVD)(8).The most recent 2023 Chinese Guidelines for Lipid Management and the 2019 ESC/EAS Guidelines for Lipid Management both underscore that LDL-C stands as the primary interventional target for preventing and treating ASCVD. Simultaneously, these guidelines stratify ASCVD patients based on risk levels. For individuals at extremely high risk of ASCVD, the guidelines advocate maintaining LDL-C levels below < 1.8 mmol, whereas for those classified as having hyper high-risk ASCVD, the recommended target for low-density lipoprotein levels is set below 1.4 mmol/L(9, 10).Statin medications constitute the cornerstone of lipid-lowering therapy, with moderately potent statins being the preferred therapeutic strategy for lipid management among the Chinese population(9).Nevertheless, a significant number of ASCVD patients have not received optimal treatment and have failed to achieve the LDL-C targets outlined in the guidelines. This circumstance contributes to an elevated risk of recurrent ASCVD events among these individuals(11, 12).Statin medications are the preferred therapeutic agents for managing lipid abnormalities; however, their efficacy is influenced by genetic polymorphism(13, 14).

Organic anion transporting polypeptide 1B3 (OATP1B3) is a constituent of the organic anion transporting polypeptide (OATP) family, facilitating the transportation of various endogenous and exogenous substances. Transporter proteins play an indispensable role in the translocation of drugs from the bloodstream to hepatocytes, a prerequisite for hepatic drug action or intracellular metabolism before excretion. Consequently, uptake transporters such as members of the organic anion transporting polypeptide (OATP) family serve as pivotal determinants of drug pharmacokinetics. Within hepatocytes, OATP family members OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are highly and nearly entirely expressed. Substrates of OATP1B1 and OATP1B3 encompass antibiotics and HMG-CoA reductase inhibitors (statin medications)(15, 16).Presently, it is established that SLCO1B3 plays a pivotal role in the absorption and transport of statins. Hence, the principal focus of this study revolves around investigating the impact of genetic polymorphism within SLCO1B3 on both lipid levels and the efficacy of statin therapy. Simultaneously, an exploration into the potential correlation between genetic variability in SLCO1B3 and statin sensitivity is also undertaken.

1. Subjects

This study enrolled a total of 780 patients diagnosed with coronary atherosclerotic heart disease through their initial coronary angiography at the Cardiac Center of the First Affiliated Hospital of Xinjiang Medical University, between the years 2012 and 2022. These patients had been regularly taking statin medications for a minimum of 4 weeks. Inclusion criteria were as follows: (1) Coronary angiography indicating coronary artery stenosis of at least 50% in the main coronary artery or major branch vessels; (2) Regular statin therapy for at least 4 weeks; (3) Availability of pre-statin treatment lipid levels and lipid levels after a minimum of 4 weeks of statin therapy. Exclusion criteria included: (1) Patients who had not undergone lipid testing prior to commencing statin medication; (2) Patients with missing follow-up data; (3) Patients with comorbid thyroid dysfunction, chronic liver diseases (such as cirrhosis, hepatitis), or chronic renal insufficiency; (4) Patients who experienced asymptomatic increases in creatine kinase, myalgia, rhabdomyolysis, liver impairment, or any intolerance to statin medication leading to self-discontinuation. Ethical approval for this study was granted by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (Ethics Approval No.220525-06-2305A-Y1), and all study participants provided informed consent.

2. Biochemical Parameter Analysis

Biochemical parameter analysis was conducted using the VITROS AR/AVL Clinical Chemistry System Analyzer from Newark, New Jersey, USA, at the Clinical Laboratory Department of the First Affiliated Hospital of Xinjiang Medical University. Patient-related parameters were subjected to assays both prior to the commencement of statin therapy and after a minimum of 4 weeks of statin treatment. These parameters included blood urea nitrogen (BUN), uric acid (UA), serum creatinine (Scr), fasting plasma glucose (FPG), glycated serum protein (HbA1c), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), lipoprotein(a) (Lpa), total bilirubin (Tbil), albumin (ALB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

3. Definition of Sensitive and Control Groups

We categorized participants based on the extent of LDL-C reduction after statin therapy (where 'a' represents LDL-C levels before statin usage, and 'b' represents LDL-C levels after statin usage; LDL-C reduction percentage is calculated as (a - b) / a). Those demonstrating a reduction in LDL-C levels of ≥ 50% from baseline after statin treatment were assigned to the sensitive group, while those with a reduction in LDL-C levels of < 50% from baseline were assigned to the control group.

4.SNP Detection Method

Human genomic DNA was extracted using a standard method. The SNP genotyping work was performed using a custom-by-design 48-Plex SNPscan™ Kit (Cat#:G0104; Genesky Biotechnologies Inc., Shanghai, China). This kit was developed according to patented SNP genotyping technology by Genesky Biotechnologies Inc., which was based on double ligation and multiplex fluorescence PCR. Briefly, 100–200 ng of DNA sample was first denatured at 98 ℃ for 5 min in a 10- mL reaction containing 1xDNA lysis buffer and then mixed well with a 10- mL ligation premix composed of 2 mL 103 ligase buffer, 0.5 mL ligase, 1 mL probe mix, and 7.5 mL Milli-Q water. The ligation reaction was carried out in an ABI2720 thermal cycler. Two 48-plex fluorescence PCR reactions were performed for each ligation product. PCR reactions were prepared in a 20- mL mixture containing 1xPCR master mix, 1 mL primer mix set A or set B, and 1 mL ligation product. PCR products were separated and detected by capillary electrophoresis in an ABI3730XL sequencer. Raw data were analyzed according to the information obtained for the labeling dye color and fragment size of the allele-specific ligation-PCR product. Genotyping was conducted without any knowledge regarding the subject’s case or control status. For quality control, repeated analyses were accomplished to guarantee the genotyping quality by randomly choosing 4% of samples with high DNA quality.

5. Statistical Analysis

For normally distributed continuous data, mean ± standard deviation were used for representation, and group comparisons were performed using t-tests or analysis of variance (ANOVA). For skewed distributed continuous data, the interquartile range method was employed, and group comparisons were conducted using the Mann-Whitney U test or Kruskal Wallis test. Count data were presented as proportions (rates or composition ratios), and group comparisons were assessed using the chi-squared test. Trend chi-squared test was utilized for comparisons involving ordered categorical variables. Multiple logistic regression analysis was employed to explore the correlation between SLCO1B3 genetic polymorphism and statin sensitivity, calculating adjusted odds ratios (OR) with corresponding 95% confidence intervals (95% CI). All statistical tests were two-tailed, and differences were considered statistically significant when p-values were < 0.05. All statistical analyses were performed using SPSS 27.0 for Windows.

1.Clinical and metabolic characteristic of subjects

The study encompassed a total of 780 patients diagnosed with ASCVD for the first time at the First Affiliated Hospital of Xinjiang Medical University. Among these patients, there were 408 individuals of Han ethnicity and 372 individuals of Uighur ethnicity. Within the Han group, 61.3% were male, while within the Uighur group, 75.5% were male. The average age of the Han group was 60.2 ± 11 years, and the average age of the Uighur group was 55.6 ± 8.9 years. Prior to commencing statin therapy, the Han population exhibited significantly higher levels of Tbil, ALB, HbA1c, TC, HDL-C, and APOA1 in comparison to the Uighur population. Additionally, the Han population had significantly lower levels of ALT than the Uighur population (refer to Table 1).

Table 1

Clinical and metabolic characteristic of subjects
	Han(408)	Uyghur(372)	P value
age	60.2 ± 11	55.6 ± 8.9	< 0.001
Scr(µmol/L)	75 ± 26	73.6 ± 16.9	0.40
BUN(mmol/L)	5.5 ± 1.6	5.7 ± 1.7	0.15
UA(µmol/L)	324(272,387)	328(270,379)	0.64
Tbil(µmol/L)	11.8(8.7,15.4)	9.5(7.2,12.6)	< 0.001
AST(U/L)	20.2(16.5,26.4)	19.6(16.4,26)	0.44
ALT(U/L)	20.7(14.7,30.5)	25(17.6,38.9)	< 0.001
ALB(g/L)	41.2 ± 5	39.9 ± 3.9	< 0.001
FPG(mmol/L)	6.4 ± 2.6	6.4 ± 2.9	0.88
HbA1c(%)	3.3 ± 1.9	2.7 ± 1.4	< 0.001
TG(mmol/L)	2.2 ± 1.3	2.3 ± 1.6	0.17
TC(mmol/L)	5.2 ± 1	4.9 ± 1.1	< 0.001
HDL-C(mmol/L)	1.1 ± 0.3	1 ± 0.3	< 0.001
LDL-C(mmol/L)	3.6 ± 0.8	3.5 ± 0.8	0.28
Apo A1(mmol/L)	1.2 ± 0.3	1.1 ± 0.2	< 0.001
Apo B(mmol/L)	1.1 ± 0.3	1.1 ± 0.3	0.05
Lpa(mg/dL)	161.1(90.5,277.2)	164.9(97.6,333.3)	0.18
Sex			< 0.001
Male	250(61.3)	281(75.5)
Female	158(38.7)	91(24.5)

2.Lipid profile and clinical indicators before and after atorvastatin treatment.

After at least 4 weeks of statin therapy, in the Han population, there were notable reductions in plasma levels of HbA1c, TC, TG, LDL-C, APOA1, and APOB, with no significant changes in Lpa and HDL-C levels. In the Uighur population, similar treatment duration led to significant decreases in ALT, AST, TC, TG, LDL-C, APOA1, and APOB levels, while Lpa and HDL-C levels remained unchanged(refer to Table 2).

Table 2

Lipid profile and clinical indicators before and after atorvastatin treatment.
Ethnic		At baseline	After treatment	P value
Han	Scr(µmol/L)	74.97 ± 25.96	74.11 ± 28.16	0.651
	BUN(mmol/L)	5.49 ± 1.62	5.58 ± 1.95	0.465
	UA(µmol/L)	324(272,387)	325.9(262,390.7)	0.762
	Tbil(µmol/L)	11.8(8.7,15.4)	11.1(8.3,14.8)	0.119
	AST(U/L)	20.2(16.5,26.4)	20.2(16,24.5)	0.184
	ALT(U/L)	20.7(14.7,30.5)	21.5(14.7,30)	0.843
	ALB(g/L)	41.25 ± 5	41.38 ± 4.73	0.698
	FPG(mmol/L)	6.37 ± 2.58	6.24 ± 2.46	0.479
	HbA1c(%)	3.28 ± 1.9	2.95 ± 1.69	0.014
	TG(mmol/L)	2.15 ± 1.33	1.88 ± 1.34	0.004
	TC(mmol/L)	5.16 ± 0.97	3.88 ± 1.02	< 0.001
	HDL-C(mmol/L)	1.12 ± 0.33	1.08 ± 0.29	0.113
	LDL-C(mmol/L)	3.56 ± 0.77	2.32 ± 0.76	< 0.001
	Apo A1(mmol/L)	1.24 ± 0.28	1.18 ± 0.25	< 0.001
	Apo B(mmol/L)	1.1 ± 0.26	0.83 ± 0.25	< 0.001
	Lpa(mg/dL)	161.1(90.5,277.2)	156.4(83.5,300.1)	0.792
Uyghur	Scr(µmol/L)	73.63 ± 16.91	74.07 ± 18.31	0.736
	BUN(mmol/L)	5.67 ± 1.71	5.7 ± 1.78	0.795
	UA(µmol/L)	328(270,379)	319.09 ± 93.89	0.082
	Tbil(µmol/L)	9.5(7.2,12.6)	11.64 ± 7.33	0.29
	AST(U/L)	19.6(16.4,26)	18.3(15.9,23.6)	0.011
	ALT(U/L)	25(17.6,38.9)	22.4(16.7,32.1)	0.002
	ALB(g/L)	39.86 ± 3.9	39.98 ± 4.53	0.7
	FPG(mmol/L)	6.4 ± 2.89	6.63 ± 3.16	0.296
	HbA1c(%)	2.66 ± 1.4	2.65 ± 1.48	0.963
	TG(mmol/L)	2.29 ± 1.56	1.96 ± 1.35	0.002
	TC(mmol/L)	4.91 ± 1.07	4.07 ± 1.14	< 0.001
	HDL-C(mmol/L)	0.96 ± 0.26	0.98 ± 0.26	0.505
	LDL-C(mmol/L)	3.5 ± 0.82	2.46 ± 0.77	< 0.001
	Apo A1(mmol/L)	1.13 ± 0.22	1.1 ± 0.27	0.04
	Apo B(mmol/L)	1.06 ± 0.27	0.89 ± 0.27	< 0.001
	Lpa(mg/dL)	164.9(97.6,333.3)	158(87.6,319.9)	0.33

3. Impact of SNP1(rs2117032) on Lipid Profile and Liver Function in Han Population

In the Han population, before statin therapy, for SNP1 (rs2117032), the three genotypes (CC, CT, and TT), two alleles (C and T), the dominant model (TT vs. CC + CT), the recessive model (CC vs. CT + TT), and the additive model (CT vs. CC + TT) showed no significant differences in lipid levels and liver function except for APOB. However, there were statistical differences in SNP1 genotypes (P = 0.034), recessive model (P = 0.038), and additive model (P = 0.02) concerning APOB levels before statin treatment. After at least 4 weeks of statin therapy in the Han population, for SNP1, the three genotypes, two alleles, and all three models showed no significant differences in lipid levels and liver function, except for APOB, Lpa, and AST. However, there were statistical differences in SNP1 genotypes (P = 0.028) and recessive model (P = 0.01) regarding APOB levels after statin therapy. The recessive model (P = 0.033) of SNP1 showed statistical differences in Lpa levels after statin therapy. The dominant model (P = 0.02) and allele (P = 0.022) of SNP1 exhibited statistical differences in AST levels after statin therapy. For SNP1, the three genotypes, two alleles, and all three models showed no differences in the reduction rates of other lipids and liver function, except for LDL-C reduction rates. The average reduction rate of LDL-C for the recessive model (CT + TT) of SNP1 was 33.44%, significantly lower than the CC genotype's average LDL-C reduction rate of 38.77% (P = 0.019). The average LDL-C reduction rate for the C allele of SNP1 was 35.93%, higher than the T allele's average LDL-C reduction rate of 33.22% (P = 0.027)(refer to Additional file 1).

4.Impact of SNP1(rs2117032) on Lipid Profile and Liver Function in Uighur Population

In the Uighur population, before statin therapy, for SNP1 (rs2117032), the three genotypes, two alleles, and three models showed no significant differences in lipid levels and liver function, except for Tbil. However, the dominant model (P = 0.03) of SNP1 exhibited statistical differences in Tbil levels before statin therapy. After at least 4 weeks of statin therapy in the Uighur population, for SNP1, the three genotypes, two alleles, and three models showed no significant differences in all lipid levels and liver function levels. The three genotypes, two alleles, and three models of SNP1 showed no differences in all lipid and liver function reduction rates(refer to Additional file 2).

5.Impact of SNP2 (rs3764006) on Lipid Profile and Liver Function in Han Population

In the Han population, before taking statins, SNP2 (rs3764006) showed no significant differences in lipid levels or liver function, except for ALT and Tbil. The dominant model of SNP2 (GG vs. AA + AG) exhibited statistical differences in ALT and TBIL levels before statin therapy (p = 0.023 and p = 0.036, respectively). After at least 4 weeks of statin therapy, the A allele of SNP2 (P = 0.038) showed a significant difference in LDL-C levels. SNP2 genotypes (P = 0.033), the recessive model (P = 0.018), and the A allele (P = 0.009) demonstrated statistical differences in APOB levels. SNP2 genotypes (P = 0.028) and the dominant model (P = 0.019) exhibited statistical differences in Lpa levels. The A allele of SNP2 (P = 0.045) showed a statistical difference in AST levels. The average LDL-C reduction rate for SNP2 genotype AA was 32.27%, for AG genotype 36.19%, and for GG genotype 41.54%. The mutated genotype (GG) led to a significantly higher LDL-C reduction rate (P = 0.009). The average LDL-C reduction rate for the dominant model (AA + AG) of SNP2 was 33.87%, significantly lower than the GG genotype's average reduction rate of 41.54% (P = 0.029). The recessive model (AG + GG) of SNP2 exhibited an average LDL-C reduction rate of 36.95%, significantly higher than the AA genotype's 32.27% (P = 0.007). The A allele of SNP2 had an average LDL-C reduction rate of 33.27%, significantly lower than the G allele's 37.53%. Additionally, the A allele of SNP2 showed an average APOB reduction rate of 21.12%, significantly lower than the G allele's 25.32% (P = 0.04)(refer to Additional file 3).

6.Impact of SNP2 (rs3764006) on Lipid Profile and Liver Function in Uighur Population

In the Uighur population, before taking statins, SNP2 (rs3764006) did not show significant differences in lipid levels or liver function, except for APOA. The recessive model (P = 0.04) and the additive model (P = 0.023) of SNP2 exhibited statistical differences in APOA levels before statin therapy. After at least 4 weeks of statin therapy, SNP2 genotypes, allele types, and models did not show significant differences in any lipid levels or liver function. Similarly, there were no significant differences in the reduction rates of lipid levels and liver function for SNP2 genotypes, allele types, and models(refer to Additional file 4).

7.Impact of SNP3 (rs4149117) on Lipid Profile and Liver Function in Han Population

In the Han population, before taking statins, SNP3 (rs4149117) did not exhibit significant differences in lipid levels or liver function, except for LDL-C, TC, and TG. The recessive model (P = 0.022), additive model (P = 0.025), and allele type (P = 0.05) of SNP3 showed statistical differences in LDL-C levels before statin therapy. SNP3 genotypes (P = 0.005), dominant model (P = 0.009), recessive model (P = 0.009), and allele type (P = 0.002) exhibited statistical differences in TG levels before statin therapy. SNP3 genotypes (P = 0.027), recessive model (P = 0.007), additive model (P = 0.012), and allele type (P = 0.018) showed statistical differences in TC levels before statin therapy. After at least 4 weeks of statin therapy, SNP3 genotypes, allele types, and models did not show significant differences in other lipid levels and liver function, except for TG, ALT, and AST. SNP3's recessive model (P = 0.035) and allele type (P = 0.048) showed statistical differences in TG levels after statin therapy, while SNP3 genotypes (P = 0.045), recessive model (P = 0.013), additive model (P = 0.034), and allele type (P = 0.018) exhibited statistical differences in ALT levels after statin therapy. Similarly, SNP3 genotypes (P = 0.022), recessive model (P = 0.01), and allele type (P = 0.006) showed statistical differences in AST levels after statin therapy. SNP3 genotypes, allele types, and models did not show significant differences in reduction rates of lipid levels and liver function(refer to Additional file 5).

8.Impact of SNP3 (rs4149117) on Lipid Profile and Liver Function in Uighur Population

In the Uighur population, before taking statins, SNP3 (rs4149117) did not show significant statistical differences in lipid levels or liver function for its three genotypes, two allele types, and three models. After at least 4 weeks of statin therapy, SNP3's genotypes, allele types, and models exhibited no significant statistical differences in both lipid levels and liver function. SNP3's genotypes, allele types, and models also showed no significant differences in reduction rates of lipid levels and liver function, except for AST. The allele type of SNP3 (P = 0.044) exhibited a statistically significant difference in the average reduction rate of AST levels(refer to Additional file 6).

9.Impact of SNP4 (rs2417940) on Lipid Profile and Liver Function in Han Population

In the Han population, before taking statins, SNP4 (rs2417940) exhibited no significant statistical differences in lipid levels or liver function for its three genotypes, two allele types, and three models, except for Tbil. The dominant model (P = 0.047) and allele type (P = 0.031) of SNP4 showed a statistically significant difference in Tbil levels before statin therapy. After at least 4 weeks of statin therapy, SNP4's genotypes, allele types, and models showed no significant statistical differences in lipid levels and liver function, except for TG and Tbil. The allele type of SNP4 (P = 0.047) exhibited a statistically significant difference in TG levels after statin therapy. The recessive model (P = 0.034) and allele type (P = 0.017) of SNP4 showed a statistically significant difference in Tbil levels after statin therapy. SNP4's three genotypes, two allele types, and three models showed no significant differences in reduction rates of lipid levels and liver function(refer to Additional file 7).

10.Impact of SNP4(rs2417940)on Lipid Profile and Liver Function in Uighur Population

Among the Uighur ethnic group, prior to commencing statin therapy, there existed no discernible statistical distinctions across the three genotypic variants, two allelic forms, and three models of Snp4 in relation to lipid levels and hepatic function. Following a minimum of four weeks of statin intervention, the three genotypic variants, two allelic forms, and three models of Snp4 continued to exhibit an absence of notable statistical variances in both lipid levels and hepatic function. Notably, within the concealed model (CT + TT), the genotypic category demonstrated a substantial average reduction rate in LDL-C of 32.13%, markedly surpassing the average LDL-C reduction rate of 27.79% observed in the CC genotypic category (P = 0.034). Meanwhile, the C allelic form of SNP4 displayed an average LDL-C reduction rate of 28.39%, distinctly lower than the corresponding T allelic form's average LDL-C reduction rate of 32.16% (P = 0.036)(refer to Additional file 8).

11.Presents baseline data for statin sensitivity-grouped Han and Uyghur populations

Based on the LDL-C reduction rate, we categorized individuals with LDL-C reduction rates ≥ 50% as the sensitive group, and those with LDL-C reduction rates > 50% as the control group. Following this grouping approach, among the Han ethnic population, we observed that prior to statin therapy, the sensitive group exhibited elevated HDL-C levels compared to the control group (P = 0.048), while no notable differences were observed in other parameters. In the Uighur ethnic group, prior to statin therapy, the sensitive group displayed significantly higher levels of BUN, HbA1c, TC, LDL-C, and APOA in contrast to the control group. Conversely, the sensitive group exhibited lower levels of Lpa compared to the control group(refer to Table 3).

Table 3

Presents baseline data for Han and Uyghur populations grouped based on statin sensitivity.
	Han(408)			Uyghur(372)
	Sensitive (N = 78)	Contro(N = 330)	P	Sensitive(N = 46)	Control(N = 326)	P
age	59.4 ± 10.4	60.4 ± 11.2	0.463	55.5 ± 8.8	55.6 ± 9	0.95
Scr	74.4 ± 16.4	75.1 ± 27.8	0.816	72.9 ± 14.5	73.7 ± 17.2	0.76
BUN	5.4 ± 1.4	5.5 ± 1.7	0.677	6.1 ± 2	5.6 ± 1.7	0.04
UA	335.6(271.5,385.3)	324(272,387.5)	0.48	318.4(264.9,378.3)	328(270.8,379.1)	0.933
Tbil	11.5(8.7,15.6)	11.8(8.7,15.4)	0.895	8.6(7.2,12)	9.7(7.2,12.9)	0.365
AST	19.6(16,26.2)	20.3(16.6,26.9)	0.369	19.1(14.9,25.1)	19.7(16.5,26.4)	0.276
ALT	18.7(14,27.3)	21.4(15.1,31.9)	0.095	23.8(16.9,32.4)	26.2(18,39.1)	0.266
ALB	41.8 ± 3.9	41.1 ± 5.2	0.295	40.8 ± 3.6	39.7 ± 3.9	0.08
FPG	6.7 ± 2.9	6.3 ± 2.5	0.253	7.1 ± 2.9	6.3 ± 2.9	0.09
HbA1c	3.4 ± 2	3.2 ± 1.9	0.466	3.2 ± 2	2.6 ± 1.3	0.01
TG	2.1 ± 1	2.2 ± 1.4	0.776	2.7 ± 2.3	2.2 ± 1.4	0.07
TC	5.3 ± 0.9	5.1 ± 1	0.226	5.3 ± 1.2	4.9 ± 1	0.01
HDL-C	1.2 ± 0.5	1.1 ± 0.3	0.048	1 ± 0.3	1 ± 0.3	0.31
LDL-C	3.7 ± 0.7	3.5 ± 0.8	0.167	3.8 ± 0.9	3.5 ± 0.8	0.02
Apo A1	1.3 ± 0.2	1.2 ± 0.3	0.39	1.2 ± 0.2	1.1 ± 0.2	0.02
Apo B	1.1 ± 0.2	1.1 ± 0.3	0.754	1.1 ± 0.3	1.1 ± 0.3	0.28
Lpa	164.4(94.6,231.7)	160(90,282.6)	0.585	127.7(71.6,199.1)	180.8(101.1,355.1)	0.002
Sex			0.063			0.522
Male	55(70.5)	195(59.1)		33(71.7)	248(76.1)
Female	23(29.5)	135(40.9)		13(28.3)	78(23.9)

12.Association of SLCO1B3 Gene Polymorphism with Statin Sensitivity in Han and Uyghur Populations

All genotype frequencies were found to be in accordance with Hardy-Weinberg equilibrium (HWE) (p < 0.05). The distribution of SNP1 (rs2117032) genotypes, alleles, dominant models, recessive models, and additive models showed no significant differences between the sensitive and control groups, whether among the Han or Uighur populations. In the Han ethnic group, for SNP2 (rs3764006), significant differences were observed in the distribution of genotypes (P = 0.013), alleles (P = 0.003), recessive model (P = 0.005), and additive model (P = 0.034) between the sensitive and control groups. However, these differences were not observed in the Uighur population. In the case of SNP3 (rs4149117), the distribution of the three genotypes, two alleles, and three models in the sensitive and control groups within the Han population showed no significant differences. Conversely, for the Uighur population, SNP3 exhibited notable differences in the distribution of the recessive model (P = 0.029), additive model (P = 0.047), and allele frequency (P = 0.03) between the sensitive and control groups. As for SNP4 (rs2417940), the distribution of its three genotypes, two alleles, and three models demonstrated no significant differences between the sensitive and control groups, irrespective of whether it was among the Han or Uighur ethnicities(refer to Table 4 and Table 5).

Table 4

Association of SLCO1B3 Gene Polymorphism with Statin Sensitivity in Han Populations
Variants	Model		Sensitive n(%) (N = 78)	Control n(%) (N = 330)	P-value	Sensitive P(H-W)	Control P(H-W)
rs2117032(SNP1)	Genotypes	CC	18(0.23)	52(0.16)	0.21	0.99	0.58
		CT	39(0.50)	164(0.50)
		TT	21(0.27)	114(0.35)
	Dominant model	CC + CT	57(0.73)	216(0.65)	0.2
	Dominant model	TT	21(0.27)	114(0.35)	0.2
	Recessive model	TT + CT	60(0.77)	278(0.84)	0.12
	Recessive model	CC	18(0.23)	52(0.16)	0.12
	Additive model	CC + TT	39(0.5)	166(0.5)	0.96
	Additive model	CT	39(0.5)	164(0.5)	0.96
	Alleles	C allele	75(0.48)	268(0.52)	0.08
	Alleles	T allele	81(0.41)	392(0.59)	0.08
rs3764006(SNP2)	Genotypes	AA	32(0.41)	194(0.59)	0.013	0.5	0.99
		AG	38(0.49)	118(0.36)
		GG	8(0.1)	18(0.06)
	Dominant model	AA + AG	70(0.9)	312(0.95)	0.118
	Dominant model	GG	8(0.1)	18(0.05)	0.118
	Recessive model	AG + GG	46(0.59)	136(0.41)	0.005
	Recessive model	AA	32(0.41)	194(0.59)	0.005
	Additive model	AA + GG	40(0.51)	212(0.64)	0.034
	Additive model	AG	38(0.49)	118(0.36)	0.034
	Alleles	A allele	102(0.65)	506(0.77)	0.003
	Alleles	G allele	54(0.35)	154(0.23)	0.003
rs4149117(SNP3)	Genotypes	GG	44(0.56)	185(0.57)	0.95	0.94	0.68
		GT	29(0.37)	123(0.38)
		TT	5(0.06)	18(0.06)
	Dominant model	GG + GT	73(0.94)	308(0.94)	0.76
	Dominant model	TT	5(0.06)	18(0.06)	0.76
	Recessive model	TT + GT	34(0.44)	141(0.43)	0.96
	Recessive model	GG	44(0.56)	185(0.57)	0.96
	Additive model	GG + TT	49(0.63)	203(0.62)	0.93
	Additive model	GT	29(0.37)	123(0.38)	0.93
	Alleles	G allele	117(0.75)	493(0.76)	0.87
	Alleles	T allele	39(0.25)	159(0.24)	0.87
rs2417940(SNP4)	Genotypes	CC	49(0.63)	224(0.68)	0.6	0.73	0.81
		CT	25(0.32)	95(0.29)
		TT	4(0.05)	11(0.03)
	Dominant model	CC + CT	74(0.95)	319(0.97)	0.45
	Dominant model	TT	4(0.05)	11(0.03)	0.45
	Recessive model	TT + CT	29(0.37)	106(0.32)	0.4
	Recessive model	CC	49(0.63)	224(0.68)	0.4
	Additive model	CC + TT	53(0.68)	235(0.71)	0.57
	Additive model	CT	25(0.32)	95(0.29)	0.57
	Alleles	C allele	123(0.79)	543(0.82)	0.32
	Alleles	T allele	33(0.21)	117(0.18)	0.32

Table 5

Association of SLCO1B3 Gene Polymorphism with Statin Sensitivity in Uyghur Populations
Variants	Model		Sensitive n(%) (N = 46)	Control, n (%) (N = 326)	P-value	Sensitive P(H-W)	Control P(H-W)
rs2117032(SNP1)	Genotypes	CC	6(0.13)	46(0.14)	0.55	0.26	0.72
		CT	26(0.57)	157(0.48)
		TT	14(0.3)	123(0.38)
	Dominant model	CC + CT	32(0.7)	203(0.62)	0.34
	Dominant model	TT	14(0.3)	123(0.38)	0.34
	Recessive model	TT + CT	40(0.87)	280(0.86)	0.85
	Recessive model	CC	6(0.13)	46(0.14)	0.85
	Additive model	CC + TT	20(0.43)	169(0.52)	0.29
	Additive model	CT	26(0.57)	157(0.48)	0.29
	Alleles	C allele	38(0.41)	249(0.38)	0.57
	Alleles	T allele	54(0.59)	403(0.62)	0.57
rs3764006(SNP2)	Genotypes	AA	35(0.76)	225(0.69)	0.45	0.85	0.53
		AG	11(0.24)	93(0.29)
		GG	0(0)	7(0.02)
	Dominant model	AA + AG	46(1)	318(0.98)	0.32
	Dominant model	GG	0(0)	7(0.02)	0.32
	Recessive model	AG + GG	11(0.24)	100(0.31)	0.34
	Recessive model	AA	35(0.76)	225(0.69)	0.34
	Additive model	AA + GG	35(0.76)	232(0.71)	0.51
	Additive model	AG	11(0.24)	93(0.29)	0.51
	Alleles	A allele	81(0.88)	543(0.84)	0.27
	Alleles	G allele	11(0.12)	107(0.17)	0.27
rs4149117(SNP3)	Genotypes	GG	22(0.49)	214(0.66)	0.09	0.58	0.35
		GT	20(0.44)	97(0.3)
		TT	3(0.07)	15(0.05)
	Dominant model	GG + GT	42(0.93)	311(0.95)	0.55
	Dominant model	TT	3(0.07)	15(0.05)	0.55
	Recessive model	TT + GT	23(0.51)	112(0.34)	0.029
	Recessive model	GG	22(0.49)	214(0.66)	0.029
	Additive model	GG + TT	25(0.56)	229(0.7)	0.047
	Additive model	GT	20(0.44)	97(0.3)	0.047
	Alleles	G allele	64(0.71)	525(0.81)	0.03
	Alleles	T allele	26(0.29)	127(0.2)	0.03
rs2417940(SNP4)	Genotypes	CC	29(0.63)	244(0.75)	0.24	0.97	0.22
		CT	15(0.33)	73(0.22)
		TT	2(0.04)	9(0.03)
	Dominant model	CC + CT	44(0.96)	317(0.97)	0.55
	Dominant model	TT	2(0.04)	9(0.03)	0.55
	Recessive model	TT + CT	17(0.37)	82(0.25)	0.09
	Recessive model	CC	29(0.63)	244(0.75)	0.09
	Additive model	CC + TT	31(0.67)	253(0.78)	0.13
	Additive model	CT	15(0.33)	73(0.22)	0.13
	Alleles	C allele	73(0.79)	561(0.86)	0.09
	Alleles	T allele	19(0.21)	91(0.14)	0.09

13. Linkage Disequilibrium (LD) Test and Haplotype Construction

In Han population,LD analysis of the SLCO1B3 gene was performed. We identified that these four SNPs are located in the same haplotype block. Except for rs4149117(SNP3) and rs2417940(SNP4), all the r2 values of SNPs were below 0.5, which means that we could not construct haplotypes of SNP3 and SNP4 simultaneously. In addition, because the minor allele frequency (MAF) of SNP3 is larger than that of SNP4.Finally,we used rs2117032 (SNP1),rs3764006(SNP2),and rs4149117(SNP3) to construct the haplotypes.(refer to Fig. 1)

Likewise, in the Uyghur population, employing the same approach, we used rs2117032 (SNP1), rs3764006 (SNP2), and rs2417940 (SNP4) as the foundation for haplotype construction(refer to Fig. 2) .

14.The relationship between SLCO1B3 gene haplotypes and statin sensitivity in Han and Uyghur populations.

In Han population, We established the haplotypes by combining SNP1,SNP2 and SNP3. Te distribution of haplotypes constructed by SNP1-SNP2–SNP3 between the statin sensitivity and control groups was analysed. Te haplotype distributions of C-G-G(H3) was significantly different between the two groups (p < 0.05). Te frequencies of the H3 haplotype were signifcantly higher in the statin sensitivity than in the control group (OR = 1.861, 95%CI:1.178 ~ 2.939, p = 0.007).

Table 6

Correlation between SLCO1B3 haplotype and statin sensitivity in the Han population
Haplotype	SNP1	SNP2	SNP3	Sensitive(freq)	Control(freq)	OR(95%CI)	P value
H1	C	A	G	7.19(0.046)	35.99(0.055)	0.824 [0.363 ~ 1.871]	0.643
H2	C	A	T	14.98(0.096)	86.51(0.133)	0.692 [0.388 ~ 1.234]	0.210
H3	C	G	G	31.49(0.202)	77.75(0.119)	1.861 [1.178 ~ 2.939]	0.007
H4	C	G	T	21.34(0.137)	62.75(0.096)	1.482 [0.876 ~ 2.508]	0.140
H5	T	A	G	77.15(0.495)	372.04(0.571)	0.730 [0.514 ~ 1.037]	0.078
H6	T	A	T	2.68(0.017)	7.45(0.011)	1.507 [0.369 ~ 6.152]	0.565
H7	T	G	G	1.17(0.007)	7.22(0.011)	0.672 [0.094 ~ 4.782]	0.690
H8	T	G	T	0.00(0.000)	2.29(0.004)	-	-

In Uyghur population,We established the haplotypes by combining SNP1,SNP2 and SNP4.Te distribution of haplotypes constructed by SNP1-SNP2-SNP4 between the statin sensitivity and control groups was analysed. Te haplotype distributions of T-A-T(H6) was significantly different between the two groups (p < 0.05). Te frequencies of the H6 haplotype were signifcantly higher in the statin sensitivity than in the control group (OR = 4.906, 95%CI:1.549 ~ 15.541, p = 0.0029).

Table 7

Correlation between SLCO1B3 haplotype and statin sensitivity in the Uyghur population
Haplotype	SNP1	SNP2	SNP4	Sensitive(freq)	Control(freq)	OR(95%CI)	P value
H1	C	A	C	19.45(0.211)	109.93(0.169)	1.317 [0.767 ~ 2.262]	0.317
H2	C	A	T	7.55(0.082)	38.89(0.060)	1.406 [0.624 ~ 3.166]	0.409
H3	C	G	C	4.55(0.049)	56.61(0.087)	0.545 [0.205 ~ 1.455]	0.219
H4	C	G	T	6.44(0.070)	43.57(0.067)	1.049 [0.445 ~ 2.472]	0.914
H5	T	A	C	49.00(0.533)	386.66(0.595)	0.776 [0.501 ~ 1.203]	0.256
H6	T	A	T	5.00(0.054)	7.52(0.012)	4.906 [1.549 ~ 15.541]	0.003
H7	T	G	C	0.00(0.000)	6.80(0.010)	-	0.325
H8	T	G	T	0.00(0.000)	0.02(0.000)	-	-

15.Potential Independent Impact of SLCO1B3 Gene Polymorphisms on Statin Sensitivity Analyzed Using Logistic Regression

To ascertain the potential independent impact of SLCO1B3 gene polymorphisms on statin sensitivity, we conducted an analysis while controlling for covariates such as FPS, TG, TC, HDL-C, LDL-C, APOA, APOB, and Lpa. Importantly, no evidence of collinearity was observed within the regression models. Notably, in the Han population, the recessive model (AG + GG vs AA) and additive model (AA + GG vs AG) of Snp2 (rs3764006) demonstrated a notable correlation with statin sensitivity. Specifically, in the recessive model, the AG + GG genotype exhibited a 2.05-fold increased likelihood of statin sensitivity compared to the AA genotype (OR = 2.05, 95% CI = 1.23–3.43, P = 0.006). In the additive model of SNP2, the likelihood of statin sensitivity was 44% lower in individuals with the AA + GG genotype compared to those with the AG genotype (OR = 0.56, 95% CI = 0.34–0.93, P = 0.024).Similarly, in the Uyghur population, the recessive model (TT + GT vs GG) and additive model (GG + TT vs GT) of Snp3 (rs4149117) exhibited a significant correlation with statin sensitivity. In the recessive model, individuals with the GT + TT genotype had a 2.21-fold increased likelihood of statin sensitivity compared to those with the GG genotype (OR = 2.21, 95% CI = 1.13–4.32, P = 0.02). Additionally, in the additive model of SNP3, the likelihood of statin sensitivity was 49% lower in individuals with the GG + TT genotype compared to those with the GT genotype (OR = 0.51, 95% CI = 0.26–0.99, P = 0.047).

Table 8

Multiple logistic regression analysis of SLCO1B3 gene polymorphisms and statin drug sensitivity.
snp	Risk factors	Han			Uyghur
snp	Risk factors	OR	95%CI	P vale	OR	95%CI	P vale
rs3764006(SNP2)	Recessive model(AG + GG)vs(AA)	2.05	(1.23, 3.43)	0.006	0.65	(0.31, 1.38)	0.262
rs3764006(SNP2)	Additive model (AA + GG)vs(AG)	0.56	(0.34, 0.93)	0.024	1.43	(0.67, 3.05)	0.353
rs4149117(SNP3)	Recessive model(TT + GT)vs(GG)	0.91	(0.54, 1.53)	0.719	2.21	(1.13, 4.32)	0.02
rs4149117(SNP3)	Additive model (GG + TT)vs(GT)	1.15	(0.68, 1.95)	0.607	0.51	(0.26, 0.99)	0.047

The following factors were adjusted for: FPS, TG, TC, HDL-C, LDL-C, APOA, APOB, and Lpa.

This study delves into the impact of four specific SNP loci within SLCO1B3 on pre-statin oral plasma lipid profiles in both the Chinese Han and Uyghur populations. Furthermore, we investigate the influence of these SNP loci on lipid-lowering responses following statin administration within these two populations. Concurrently, we aim to elucidate any potential correlation between the four SNP loci of SLCO1B3 and statin drug sensitivity.

Subsequent investigations within significant clinical trials such as ACCESS, PRINCE, PROSPER, JUPITER, and TNT have consistently demonstrated that patients undergoing statin therapy witness notable lipid alterations as early as the fourth week of treatment initiation. Moreover, beyond this initial period, lipid levels tend to remain relatively stable. It is worth noting that even among patients adhering well to treatment and undergoing standardized therapeutic protocols, variations in the extent of LDL-C reduction persist (17–21).Within the same cohort, the magnitude of LDL-C reduction induced by statin therapy varies significantly, ranging from 31–63%(22).

Our study revealed that in both Han and Uyghur populations, statin therapy effectively lowered levels of TC, TG, LDL-C, APOA1, and APOB, while Lpa and HDL-C plasma concentrations remained unchanged before and after treatment, aligning with the consensus of most research findings. Interestingly, our investigation also uncovered a notable reduction in ALT and AST levels among the Uyghur population after statin treatment, with significant statistical differences. This intriguing observation suggests the possibility of a higher tolerance to statins among the Uyghur ethnic group, warranting further investigation.

The SLC superfamily comprises organic anion transporting polypeptides (OATP/SLCO) and statin drugs are substrates for these members. Among them, SLCO1B3, a member of the SLC superfamily, is specifically expressed on the sinusoidal membrane of hepatocytes, playing a crucial role in the uptake, transport, and metabolism of drugs. Consequently, alterations in the activity or expression of transport proteins on the hepatocyte surface can impact the absorption of statin drugs, resulting in variations in their lipid-lowering efficiency.

The point mutation rs2117032 is located in the intronic region downstream of the SLCO1B3 gene at chr12:2092118. Our study reveals significant impacts of SNP1 (rs2117032) in the Han population, affecting pre-statin levels of APOB and subsequently influencing post-statin levels of APOB, Lpa, and AST. Furthermore, SNP1's genetic polymorphism significantly affects the LDL-C reduction rate after statin therapy. However, these effects were not observed in the Uyghur population. Instead, in the Uyghur population, SNP1 was found to influence Tbil levels, consistent with previous research linking rs2117032 polymorphism to serum bilirubin levels. While direct effects of rs2117032 on lipid levels have not been reported, studies have highlighted the role of SLCO-encoded organic anion transporting polypeptides (OATPs) in cellular uptake of various compounds, including androgens. Notably, the nucleotide polymorphism of SLCO1B3 has been shown to alter the efficiency of androgen transport(23),The influence of androgens on lipid metabolism is noteworthy. Therefore, further investigation is warranted to ascertain whether rs2117032 exerts an impact on lipid profiles.

SNP2 (rs3764006) is situated downstream of the SLCO1B3 gene at chr12:20901435. Currently, limited research exists regarding this SNP locus, and its impact on lipid levels and statin efficacy remains unexplored. Our study unveils correlations within the Han population. Specifically, SNP2 (rs3764006) is associated with pre-atorvastatin TBil and ALT levels. Additionally, SNP2 polymorphism correlates with post-atorvastatin LDL-C, APOB, Lpa, and AST levels. Importantly, our research highlights the significant influence of SNP2 polymorphism on the rate of decline in LDL-C and APOB following atorvastatin usage. Notably, these effects of SNP2 are absent within the Uighur population. Among Uighur individuals, SNP2's impact on pre-atorvastatin APOA levels is observed, adding complexity to our findings.

SNP3 (rs4149117) is situated upstream of the SLCO1B3 gene at chr12:20858546. Studies indicate a correlation between rs4149117 and the response to total cholesterol reduction(24).Our study reveals that in the Han population, SNP3 (rs4149117) significantly affects pre-atorvastatin LDL-C, TC, and TG levels. Post-atorvastatin, SNP3 also notably impacts TG, ALT, and AST levels. These effects are absent in the Uighur population, except for SNP3's influence on the average post-statin AST reduction among Uighurs.

SNP4 (rs2417940) is positioned upstream of the SLCO1B3 gene at chr12:20864941. Current research has established a significant impact of rs2417940 on bilirubin levels in the population(25, 26).Our study also uncovers that within the Han population, SNP4 (rs2417940) significantly affects pre-atorvastatin Tbil levels. Moreover, SNP4 significantly influences post-atorvastatin TG and Tbil levels. These effects are absent in the Uighur population. Among the Uighur cohort, we observed a significant impact of SNP4 on the average post-statin LDL-C reduction rate.

To further delve into the correlation between SLCO1B3 gene polymorphisms and statin efficacy, we employed the reduction percentage of LDL-C after statin treatment as our grouping criterion. We categorized individuals based on whether their post-statin LDL-C decrease from baseline was ≥ 50% (sensitive group) or < 50% (control group). Upon conducting subgroup analyses, we ascertained that SNP1 (rs2117032) does not influence statin responsiveness in either the Han or Uighur populations.Conversely, within the Han ethnic group, SNP2 (rs3764006) significantly affects statin sensitivity. In the recessive model of SNP2, the probability of statin sensitivity for AG + GG genotypes is 2.05 times that of the AA genotype (OR = 2.05, 95%CI = 1.23–3.43, P = 0.006). In the additive model of SNP2, the probability of statin sensitivity for AA + GG genotypes is 44% lower than that of the AG genotype (OR = 0.56, 95%CI = 0.34–0.93, P = 0.024). However, this impact is not evident in the Uighur population.In the Han population, SNP3 (rs4149117) does not significantly impact statin sensitivity. Yet, within the Uighur population, SNP3 notably influences statin sensitivity. In the recessive model of SNP3, the probability of statin sensitivity for GT + TT genotypes is 2.21 times that of the GG genotype (OR = 2.21, 95%CI = 1.13–4.32, P = 0.02). In the additive model of SNP3, the probability of statin sensitivity for GG + TT genotypes is 49% lower than that of the GT genotype (OR = 0.51, 95%CI = 0.26–0.99, P = 0.047).SNP4 (rs2417940) does not influence statin sensitivity in either the Han or Uighur populations.

Upon performing haplotype analysis, we found distinct patterns. Within the Han ethnic group, the frequencies of the H3 (C-G-G) haplotype were significantly elevated in the statin-sensitive cohort compared to the control group (OR = 1.861, 95%CI: 1.178–2.939, p = 0.007). Conversely, in the Uighur population, the frequencies of the H6 (T-A-T) haplotype were markedly higher in the statin-sensitive group compared to the control group (OR = 4.906, 95%CI: 1.549–15.541, p = 0.0029).

When exploring the impact of SLCO1B3 genetic variability on lipid metabolism and the efficacy of statin drugs, it is important to consider its potential clinical applications. Personalized medicine is increasingly becoming a prominent trend in the medical field due to the significant variations in drug responses among different individuals. The findings of this study provide a novel avenue for incorporating genetic information into medical decision-making.

Furthermore, genetic polymorphisms may also be associated with the occurrence of adverse drug reactions and side effects. By delving into the relationship between genetic variations and drug metabolism pathways, we can better predict which patients might experience adverse reactions, allowing for the implementation of appropriate preventive measures or adjustments to treatment plans.

However, personalized medicine faces challenges in practical implementation. Firstly, obtaining and analyzing genetic information requires specialized techniques and equipment, which may limit its widespread use in clinical settings. Secondly, although genetic polymorphisms to some extent explain individual differences in drug responses, other factors such as environment, lifestyle, and coexisting diseases can also influence drug reactions. Therefore, when incorporating genetic information into clinical decision-making, multiple factors need to be comprehensively considered.

Additionally, we need to consider the relationship between drug sensitivity and disease prognosis. The potential correlation between certain genetic variations and the risk of cardiovascular events warrants further investigation. Such studies contribute to a deeper understanding of the complex relationship between genes and diseases.

Finally, although this study obtained consistent results in two different populations, the applicability of these findings in other ethnic groups needs further validation due to differences in race and geography. Moreover, with the continuous advancement of technology, new genetic variations may be discovered, potentially impacting our understanding of SLCO1B3 genetic polymorphisms.

In conclusion, this study delves into the influence of SLCO1B3 genetic variability on lipid metabolism and the efficacy of statin drugs, paving the way for new directions in personalized medicine. However, further research is required to elucidate its molecular mechanisms, clinical applications, and interactions with other factors, ultimately leading to more precise treatment strategies and better serving the health of patients.

The genetic polymorphism of SLCO1B3 significantly impacts blood lipid levels, influences liver function to some extent, concurrently exerts a notable influence on the efficiency of statin-induced LDL-C reduction, and is also associated with statin drug sensitivity. These findings not only contribute to a deeper understanding of the role of genetic factors in the development of cardiovascular diseases and drug therapy but also provide significant insights for personalized treatment approaches. However, despite the notable results, further research is warranted to explore potential molecular mechanisms and biological significance.

ASCVD - Atherosclerotic Cardiovascular Disease

SNPs - Single Nucleotide Polymorphisms

TC - Total Cholesterol

TG - Triglycerides

LDL-C - Low-Density Lipoprotein Cholesterol

APOA1 - Apolipoprotein A1

APOB - Apolipoprotein B

HDL-C - High-Density Lipoprotein Cholesterol

Lpa - Lipoprotein(a)

ALT - Alanine Aminotransferase

AST - Aspartate Aminotransferase

TBil - Total Bilirubin

Scr - Serum Creatinine

BUN - Blood Urea Nitrogen

UA - Uric Acid

FPG - Fasting Plasma Glucose

HbA1c - Hemoglobin A1c

Ethics approval and consent to participate

Ethics Approval and Consent to Participate: This study was conducted in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (Ethics Approval No.220525-06-2305A-Y1). Written informed consent was obtained from all participants prior to their inclusion in the study.

Consent for publication

All authors have reviewed the final version of the manuscript and provided their consent for its publication

Availability of data and materials

Availability of Data and Materials: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests:

The authors declare that they have no competing interests.

Funding

⑴.National Key Research and Development Program of China (2021YFC2500600+2021YFC2500605)

⑵.National Natural Science Foundation of China（NO.81970380）

⑶.State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Fund (SKL-HIDCA-2022- XXG3)

⑷.The National Innovative Research Group Incubation Project (No. xyd2021C002).

Authors' Contributions:

Zhenyan Fu conceived and designed the study. Sifu Luo,Menglong Jin,Subinuer Jureti,Hongyu Jicollected and analyzed the data. Sifu Luodrafted the manuscript. All authors critically reviewed and approved the final version of the manuscript.

Acknowledgements：

The authors would like to extend their appreciation to the Laboratory Department of the First Affiliated Hospital of Xinjiang Medical University for their valuable assistance and support in this research

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No competing interests reported.

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Genetic Variability of SLCO1B3 and Its Influence on Lipid Levels and Statin Efficacy in Han and Uighur Populations

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Abstract

Background

Objective

Methods

Results

Conclusion

Figures

Background

Methods

1. Subjects

2. Biochemical Parameter Analysis

3. Definition of Sensitive and Control Groups

4.SNP Detection Method

5. Statistical Analysis

Result

3. Impact of SNP1(rs2117032) on Lipid Profile and Liver Function in Han Population

4.Impact of SNP1(rs2117032) on Lipid Profile and Liver Function in Uighur Population

5.Impact of SNP2 (rs3764006) on Lipid Profile and Liver Function in Han Population

9.Impact of SNP4 (rs2417940) on Lipid Profile and Liver Function in Han Population

12.Association of SLCO1B3 Gene Polymorphism with Statin Sensitivity in Han and Uyghur Populations

13. Linkage Disequilibrium (LD) Test and Haplotype Construction

15.Potential Independent Impact of SLCO1B3 Gene Polymorphisms on Statin Sensitivity Analyzed Using Logistic Regression

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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