Association of polymorphisms of ApoE, ApoA1, PCSK9 with LDL-C modification following Atorvastatin therapy in dyslipidemic patients.

Association of polymorphisms of ApoE, ApoA1, PCSK9 with LDL-C modification following Atorvastatin therapy in dyslipidemic patients. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association of polymorphisms of ApoE, ApoA1, PCSK9 with LDL-C modification following Atorvastatin therapy in dyslipidemic patients. Harmeet Rehan, Aman Singh, Lalit Gupta, Madhur Yadav This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8727328/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Dyslipidemia, a risk factor for atherosclerotic cardiovascular disease, is primarily managed by statins. Single-nucleotide polymorphisms (SNPs) may influence LDL-C reduction variability seen with statins. Treatment-naïve adult dyslipidemic patients prescribed Atorvastatin (40/80mg) were enrolled in a 12-week observational study. Lipid profiles were estimated at baseline & follow-up (week 1, 2, 4, 12), serum ApoA1, ApoE & PCSK9 were estimated at baseline and week 12. Six SNPs were genotyped at baseline. LDL-C reduction of ≥50% was compared with SNP variants. In 55 patients who completed follow-up, a decrease in LDL-C, total cholesterol, triglycerides, and ApoE was 54.55%, 40.60%, 53.1%, and 40.46%, respectively. Meanwhile, HDL-C, ApoA1 & PCSK9 levels increased by 8.76%, 17.29% &12.35% respectively. Reduction in LDL-C levels was associated with variants of rs429358(T>C) [p= 0.05], rs7412(C>T) & rs429358(T>C) combined [p= 0.13], and rs7412(C>T), rs429358(T>C), rs5069(G>A) & rs505151(G>A) combined [p= 0.18]. Genotype-based therapy may improve treatment outcomes for atorvastatin in dyslipidemia. Health sciences/Health care/Therapeutics Biological sciences/Genetics/Medical genetics Dyslipidemia atherosclerotic cardiovascular disease (ASCVD) lipid profile statin genetic variation single nucleotide polymorphism Figures Figure 1 Figure 2 Figure 3 INTRODUCTION The deaths due to non-communicable diseases (NCDs) are on the rise and account for 74% of all deaths worldwide, with 41.6% of such deaths due to cardiovascular diseases (CVD) ( 1 ). The prevalence of atherosclerotic cardiovascular disease (ASCVD) has declined in Western countries in the last two decades whereas amongst South Asians, it has increased. The multiple factors contributing to this rise are; metabolic syndrome (viz. dyslipidemia, hypertension, obesity, impaired glucose tolerance), sedentary lifestyles, unhealthy diets & habits including excess salt intake, alcohol, tobacco, urbanization, lower socio-economic status, potentially air pollution etc. ( 2 ), making the Asians prone to develop ASCVD a decade earlier with a malignant course ( 3 ). The result of which, more than half of CAD-related deaths in India occur before 50 years of age, and 25% of myocardial infarctions (MI) befall before 40 years of age ( 4 ). Apo Lipoprotein A1 (ApoA1), Apo Lipoprotein E (ApoE) and Proprotein convertase subtilisin/kexin type 9 (PCSK9) play important role in metabolism of lipids, consequently, changes in their serum concentration contributes to development of ASCVD ( 5 – 7 ). Among these risk factors for the development of ASCVD dyslipidemia is preventable. It is characterized by abnormal circulating lipid [elevation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and a decrease in the high-density lipoprotein cholesterol (HDL-C)]. ( 8 ). Nearly three-fourths of the adult Indian population has been reported to have dyslipidemia; hence, the primordial prevention and treatment of dyslipidemia may play a crucial role in reducing the burden of ASCVD ( 2 ). The management of dyslipidemia is based on risk stratification of patients using various risk calculators ( 9 , 10 ). The therapy of dyslipidemia includes a combination of therapeutic lifestyle modifications and lipid-modifying drugs (LMD) ( 11 ). The goal of the therapy is to reduce LDL-C by ≥ 50% ( 12 ). The use of statins remains the cornerstone both for the treatment of dyslipidemia and the prevention of ASCVD ( 13 ). Though inter-individual variations in the lipid-modifying response of statins are evident, their cause has not been firmly established ( 14 , 15 ). The distinct genetic makeup of the South Asian population may be one of the non-modifiable factors responsible for the early development of ASCVD. Whole genome sequencing and genome-wide association studies (GWAS) have identified various polymorphisms of genes related to lipid metabolism and transport, affecting the circulating lipid and lipoprotein levels ( 16 , 17 ). Detectable mutations in ApoA1 , ApoE , PCSK9 , and other genes contribute to the development of dyslipidemia ( 18 ). Analysis of these genetic variations may be useful for early diagnosis and treatment of dyslipidemia ( 19 ). Therefore, to optimize the benefit of statins, the present study was conducted to identify polymorphisms in ApoA1 , ApoE , and PCSK9 genes and find their association with variation in lipid-modifying response of patients. METHODOLOGY A prospective observational study was conducted on 61 treatment-naive dyslipidemic patients older than eighteen years of age prescribed high-intensity statins. Dyslipidemia was defined as patients having either raised serum LDL-C level [> 100 mg/dL (for people with CVD risk factors)], TC [≥ 200 mg/dL] and TG (> 200 mg/dL) and low HDL-C levels (< 40 mg/dL for males; 6.5), hypothyroidism, lipodystrophy, polycystic ovarian syndrome, chronic kidney disease, fatty liver, cholestasis, alcohol consumption, pregnancy, post organ transplant patients on immunosuppressants were excluded from the study. The study was conducted in accordance with the Declaration of Helsinki and after prior approval from the Institutional Ethical Committee, Lady Hardinge Medical College, (LHMC/IEC) and obtaining written informed consent from all the participants. Any treatment-associated adverse events observed/reported during the study were documented in the Suspected Adverse Drug Reaction Reporting Form. Procedures At baseline, a fasting venous blood sample (5ml) was withdrawn under all aseptic precautions, 4ml of blood was used to estimate lipid profile (TC, LDL-C, HDL-C, TG) using an autoanalyzer and ApoA1, PCSK9 & ApoE levels by sandwich Enzyme-linked immunosorbent assay (ELISA) method. ELISA kits for human serum ApoA1, PCSK9 & ApoE were procured from Shanghai Coon Koon Biotech, and the assay was conducted according to the manufacturer’s instruction manual. The remaining 1ml of blood sample was used for deoxyribonucleic acid (DNA) extraction and genotyping of candidate genes ( APOA1, PCSK9 & APOE ) by SNaPshot ® method (Fig. 1). Patients were followed -up at 1, 2, 4, and 12 weeks of initiation of LLM for refill of the prescription, estimation of lipid profile, and monitoring of ADR, if any. Additionally, at the 12-week follow-up, the estimation of serum ApoA1, PCSK9 & ApoE was repeated. Statistical analysis The responsiveness of patients to statin therapy was considered normal (NR) if the reduction in LDL-C was more than or equal to 50% from the baseline value, whereas LDL-C levels achieved < 50% were regarded as slow response (SR) ( 12 ). The biochemical parameters have been presented as mean and standard deviation. The change in lipid profile following statin therapy is presented as a percentage change. The significance of lipid profile change from baseline was calculated using paired t-test. To find the association of genetic polymorphism with percentage change in lipid profile was assessed using one-tailed & two-tailed Fisher’s exact test, where two and three variants of SNP were detected, respectively. p-value < 0.05 was considered statistically significant. RESULTS Out of 65 dyslipidemic patients screened, 61 were enrolled in the study. During the intervention, six patients were lost to follow-up (Fig. 2). The data of 55 patients is presented. Demography Out of the 55 patients, 29 (52.7%) were males and 26 (47.3%) were females. The patients were on average 44.31 ± 10.7 years old, weighing 74.97 ± 8.77 kgs. The mean dose of atorvastatin used was 44.36 mg, with atorvastatin 80 mg used by 8 patients and atorvastatin 40 mg used by 47 (85.45%) patients (Table 1). Biochemical Parameters Overall LDL-C values decreased from 176.22 ± 43.84 mg/dL at baseline to 78.64 ± 19.26 mg/dL at 12 weeks (54.55% decrease). The reduction in total cholesterol values was 40.6% at the end of follow-up from 265.47 ± 80.21 mg/dL at baseline to 151.98 ± 20.71 mg/dL at 12 weeks. HDL-C levels showed a gradual increase over time from 43.55 ± 9.52 mg/dL at baseline to 47.18 ± 10.15 at 12 weeks (8.76% increase). Triglyceride values decreased from 261.96 ± 192.70 mg/dL at baseline to 109.65 ± 41.13 mg/dL at 12 weeks (53.1% decrease). The mean baseline value of ApoA1 was 123.61 ± 30.61 ng/mL, which increased to 142.95 ± 30.92 ng/mL at 12 weeks (17.29% increase). The values of ApoE decrease from 56.51 ± 15.02 ng/mL at baseline to 32.58 ± 6.99 ng/mL at 12 weeks (40.46% decrease). Levels of PCSK9 increased by 12.35% from 403.25 ± 117.86 ng/mL at baseline to 450.86 ± 127.99 ng/mL at 12 weeks. The change in all lipid profile parameters was significant, beginning from the baseline and continuing until the end of the follow-up (p < 0.00001). No significant difference in lipid profile levels was seen between males and females (Table 2 and Table 3). Decrease in LDL-C, TC, TG & PCSK9 was 56.14%, 45.12%, 54.01% & 45.84% following atorvastatin 80 mg therapy, respectively, whereas with atorvastatin 40 mg the decrease was 54.28%, 39.83%, 52.95% & 39.54% respectively. HDL-C levels increased (11.18% vs 8.35%) more with atorvastatin 80 mg compared to 40 mg. Levels of ApoA1 & PCSK9 increased by 25.81% & 10.31% respectively, and ApoE decreased by 45.84% with atorvastatin 80 mg, whereas with atorvastatin 40mg, increases in ApoA1 & PCSK9 were 15.84% & 12.69%, respectively, and the decrease in ApoE was 39.54%. Results of mean percentage change in the lipid profile parameters at different intervals are provided in the supplementary data. Genetic Analysis I. Genotype frequency Of the total 55 dyslipidemic patients that were analyzed, genetic analysis revealed that for SNPs of ApoA1 under study, rs5069(G > A) was observed in 41 patients and rs1799837(C > T) was observed in 48 patients, for SNPs of ApoE , rs7412(C > T) was observed in 50 patients and rs429358(T > C) was observed in 52 patients, for SNPs of PCSK9 , rs505151(G > A) was observed in 53 patients and rs11591147(G > T) was observed in 55 patients. The frequency of variants GG , GA , and AA of rs5069(G > A) of ApoA1 was 97.56%, 2.44%, and 0% respectively. For the ApoA1 rs1799837(C > T), only the CC variant was observed in all 48 patients. The variants of ApoE rs7412(C > T) were observed at a frequency of 98% for CC , 2% for CT , and 0% for TT (Table 4). TT and TC variants were observed for ApoE rs429358(T > C) SNP with frequencies of 96.15% and 3.85% respectively. The frequency of GG , GA , and AA variants of PCSK9 rs505151(G > A) was 1.89%, 16.89%, and 81.13% respectively. For the PCSK9 rs11591147(G > T) SNP, all 55 patients had the GG variant (Table 4). For rs5069(G > A), the reference G allele was observed in 98.79% of samples, and the mutant A allele was observed in 1.21% of samples. The C allele was the only one observed for rs1799837(C > T). For rs7412(C > T), the C allele was predominant (99%), with the T allele present in only 1% samples. Similarly, the reference T allele was predominant (98.02%) for rs429358(T > C) as compared to the mutant C allele (1.92%). Contrastingly, for rs505151(G > A), the mutant allele A was observed in 89.62% samples while reference allele G was observed in 10.38% of samples. For rs11591147(G > T), all the samples had the reference G allele. II Genetic-phenotypic association When comparing response categories in LDL-C with variants of SNPs, variants of rs429358(T > C) of ApoE showed a statistically significant association with LDL-C reduction (> 50%) from baseline to week 12 (p = 0.05). The combined LDL-C lowering effect of SNPs of ApoE [rs7412(C > T) & rs429358(T > C)] showed association (p = 0.13) with response categories of LDL-C from baseline to week 12; similarly, a combination of SNPs which had more than one observed variant, showed association with LDL-C reduction categories (p = 0.18) at week 12. At other intervals the response categories of LDL-C either had no association or the associations were not significant (Table 5). DISCUSSION Dyslipidemia, characterized by elevated levels of lipids in the blood, is substantially affected by non-modifiable risk factors, specifically the defects in genes encoding for lipoproteins (e.g., ApoE, ApoA1), enzymes (e.g., PCSK9), and proteins involved in lipid metabolism and transport. Genome-wide association studies (GWAS) have identified hundreds of SNPs associated with lipid traits, each exerting a modest effect, but collectively contributing significantly to the risk of dyslipidemia. Understanding the genetic nature of dyslipidemia is crucial for developing personalized interventions, as individuals may carry unique combinations of genetic variants that influence their lipid levels and response to statin therapy ( 21 ). Genetic screening for risk alleles could allow identification of individuals at higher risk for dyslipidemia, enabling earlier interventions tailored to their specific genetic makeup. This knowledge could guide the development of targeted therapies, potentially improving treatment efficacy and hence reducing the risk of major cardiovascular events ( 22 ). In our study, the mean percentage reduction of LDL-C at week 1 from the baseline value was ­23.15 ± 9.25%, which further reduced by ­34.01 ± 9.63%, ­44.48 ± 11.13% and ­54.55 ± 7.88% at the end of 2, 4 & 12 weeks of atorvastatin therapy, respectively. Furthermore, atorvastatin 80 mg reduced LDL-C by 25.55% by week one, which increased to 56.14% reduction by week 12, whereas atorvastatin 40 mg reduced LDL-C by 22.74% which reached a reduction of 54.28% by week 12. A randomized, double-blind study conducted in USA by Nohria A, et al. showed that in atherosclerotic patients, atorvastatin 10 mg and 80 mg reduced LDL-C by 13% & 36% after 1 week, 27% & 44% after 2 weeks, and 36% & 50% after 4 weeks, respectively ( 23 ). Similarly, the JUPITER trial revealed that high-intensity statins reduced LDL-C by more than 50% ( 24 ). Further, in our study, the mean percentage change from baseline for TC was − 15.76 ± 9.92% at week one, -24.77 ± 11.97% at week two, -33.75 ± 11.60% at week four, and − 40.60 ± 9.24% at week 12. Atorvastain 80 mg led to a decrease of 25.55% after one week and the reduction was 56.14% by week 12, whereas atorvastatin 40 mg led to 22.74% by week one and 54.28% by week 12. Similarly, patients in the Nohria A, et al., study had TC reduction of 10% & 30% after week 1, 21% & 35% after week 2, 21% & 36% after week 3 of atorvastatin 10 mg and atorvastatin 80 mg therapy, respectively ( 23 ). The lipid lowering capacity of atorvastatin in our study suggested that its clinical benefits translated as early as after 1 week of therapy. Nohria A, et al., also reported decrease in TC throughout the follow up, but the percentage fall was lesser than LDL-C ( 23 ). The reduction in LDL-C and TC plateaued after 4 weeks and the difference in LDL-C reduction between atorvastatin 80 mg and 40 mg converged at longer intervals. In our study the mean percentage change from baseline for HDL-C was + 3.79 ± 4.94% at week one, + 6.26 ± 6.67% at week two, + 7.98 ± 8.2% at week four, + 8.76 ± 9.63% at week 12 and the mean percentage change from baseline for TG was − 22.67 ± 14.01 week one, -35.65 ± 13.27% at week two, -46.28 ± 17.23% at week four, -53.10 ± 16.75 at week 12. The CURVES study reported, HDL-C increase by atorvastatin 40 mg at week 8 as + 4.8% and the TG decrease by atorvastatin 40 mg at week 8 as -32% ( 25 ), while a study by Helmut G. Schrott, et al., reported HDL-C increase as + 2% at day 14 and TG decrease as -14% at day 7 and − 24% at day 14 of atorvastatin therapy ( 26 ). The mean percentage HDL-C increase and the TG decrease was relatively more in our study (Supplementary file). The mean change from baseline for ApoA1 at week twelve was + 17.29 ± 13.19%. Contrastingly, a meta-analysis demonstrated variable change in ApoA1 levels with statin therapy, ranging from − 5.1% to + 6.7%. ( 27 ) Comparatively, Rostam Yazdani, et al., demonstrated that aerobic exercise led to a significant increase in ApoA1 levels ( 28 ), offering a potential explanation for higher rise in serum ApoA1 levels in our study. Further as discussed previously, our study had higher increase in HDL-C and ApoA1 levels after atorvastatin therapy. Since, ApoA1 is a principal apolipoprotein component in HDL-C, and has considerable association with HDL-C ( 29 ). Offering a possible explanation for the higher ApoA1 increase seen in our study. A meta-analysis to study the association of HDL-C & ApoA1 levels with ASCVD risk outcome in patients on statin revealed a strong association. Whereas, the increase in ApoA1 levels was associated with decreased risk of CVD events but the association was not evident with the increase in HDL-C levels ( 27 ). In our study, the mean percentage reduction of ApoE levels after 12 weeks of atorvastatin therapy was − 40.46 ± 12.30%. Similarly, Ngoc-Anh Le, et al., demonstrated serum ApoE levels decrease at week four by 37% and 49% by atorvastatin 20mg and 80 mg respectively ( 30 ). ApoE facilitates reverse cholesterol transport from peripheral tissues to liver. The majority of ApoE in serum is derived from hepatocytes, whereas macrophage-specific expression of ApoE is atheroprotective ( 31 ). Paradoxically, patients with normal HDL-C with low serum ApoE levels had lower incidence of cardiovascular events compared to patients who had high ApoE with normal HDL-C levels ( 32 ). Suggesting a complex relationship of ApoE levels with CVD requiring further investigation (Supplementary file). Indians are at a higher risk to develop severe intensity of serious ASCVD with interindividual variation in responsiveness to statin ( 33 ), but a sub study of ASCOT-LLA trial by Chapman N, et al., showed no significant difference in reduction of LDL-C ( 34 ),( 35 ) and TC ( 36 ) between Whites and South Asians. Gupta M, et al., demonstrated that atorvastatin treatment for the same duration and dose produced higher increase in HDL-C and more decrease in TG levels in South Asian population compared to White population ( 36 ). The higher increase in HDL-C levels (+ 8.76 ± 9.63%) and more decrease in TG levels (-53.10 ± 16.75) in our study population could be due to dietary and genetic factors playing role in variation in two sets of population and individuals ( 37 ). The genetic analysis of blood samples in our study revealed a significant association (p = 0.05) between LDL-C reduction by atorvastatin therapy after 12 weeks and variants of rs429358(T > C) of ApoE . In our literature search, no study was available that studied the effect of rs429358(T > C) on atorvastatin-mediated LDL-C reduction. Analysis for variants of rs7412(C > T) of ApoE also did not show association with LDL-C reduction following atorvastatin therapy. Contrastingly, a GWAS by Chasman D. I, et al., showed a genome-wide level significance of LDL-C reduction by rosuvastatin due to rs7412(C > T) ( 38 ). Combination of variants of rs7412(C > T) & rs429358(T > C) were associated with a reduction in LDL-C after 12 weeks of atorvastatin therapy (p = 0.13). Similarly, Lei Zhang, et al., showed better statin lipid-lowering response in patients having e2 phenotype. The association of combination of variants of rs7412(C > T), rs429358(T > C)], rs5069(G > A) & rs505151(G > A) with LDL-C reduction was visible but non-significant (p = 0.18) (Table 5). In our study the mean percentage change in serum PCSK9 levels from baseline after twelve weeks of statin therapy was + 12.35 ± 7.52% (Table 5.3) with a rise of 47.61 ng/mL. Similarly, in a meta-analysis A. Sahebkar, et al., also demonstrated mean increase of 40.72 ng/mL in serum PCSK9 levels in patients treated with statins ( 39 ), which was lower than our study. Our results demonstrated LDL-C lowering effect of atorvastatin which was evident after week 1 (­23 ± 9.25%,) and later showcased the time dependent lipid lowering effect until at week 12 (­54.55%) (Table 5). The increased serum ApoA1 and PCSK9 levels, and decreased ApoE levels after atorvastatin therapy observed in the study may benefit ASCVD patients. A significant association of rs429358(T > C) SNPs ApoE could help in personalizing the treatment of dyslipidemia. The genetic mapping of genes associated with dyslipidemia to find patients’ responsiveness to statins which may improve statins’ preventive and therapeutic effect in CVD. CONCLUSIUON The study demonstrated that atorvastatin therapy effectively reduced LDL-C, TC, and TG while it increased HDL-C levels in dyslipidemia patients. Additionally, atorvastatin increased serum ApoA1 and PCSK9 levels, and decreased ApoE levels after 12 weeks, translating its benefit to ASCVD patients. The observed percentage changes in lipid profile parameters were significantly associated with ApoE (rs429358), highlighting the influence of genetic variants on the responsiveness of patients to statin therapy. To improve outcomes of statin therapy, incorporation of genetic screening in patient treatment plan may have a vital role in preventive and treating dyslipidemias amongst Indians. Further investigation in larger studies may shed more light on these associations. Declarations ACKNOWLEDGEMENT We greatly appreciate the contribution of Dr. Mohammed Faruq, Senior Principal Scientist, CSIR-Institute of Genomics and Integrative Biology, for providing his expertise towards the genetic analysis of the samples. COMPETING INTERESTS The authors declare no competing interests. DATA AVAILABILITY Original data may be made available upon request. References Noncommunicable diseases [Internet]. [cited 2024 Aug 28]. 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Do the Apoe–/– and Ldlr–/– Mice Yield the Same Insight on Atherogenesis? Arterioscler Thromb Vasc Biol. 2016 Sept;36(9):1734–41. Fukase T, Dohi T, Nishio R, Takeuchi M, Takahashi N, Chikata Y, et al. Paradoxical Long-Term Impact Between Serum Apolipoprotein E and High-Density Lipoprotein Cholesterol in Patients Undergoing Percutaneous Coronary Intervention. J Atheroscler Thromb. 2023 June 1;30(6):611–23. Enas EA, Varkey B, Gupta R. Expanding statin use for prevention of ASCVD in Indians: Reasoned and simplified proposals. Indian Heart J. 2020;72(2):65–9. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet. 2003;361(9364):1149–58. Chapman N, Chang CL, Caulfield M, Dahlöf B, Feder G, Sever PS, et al. Ethnic Variations in Lipid-Lowering in Response to a Statin (EVIREST): a Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Ethn Dis. 2011;21(2):150–7. Gupta M, Braga MFB, Teoh H, Tsigoulis M, Verma S. Statin Effects on LDL and HDL Cholesterol in South Asian and White Populations. J Clin Pharmacol. 2009;49(7):831–7. Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease in the Asia-Pacific Region. JACC Asia. 2021;1(3):294–302. Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial. Circ Cardiovasc Genet. 2012;5(2):257–64. Sahebkar A, Simental-Mendía LE, Guerrero-Romero F, Golledge J, Watts GF. Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes Metab. 2015;17(11):1042–55. Tables Table 1 to 5 are available in the Supplementary Files section. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table1.xlsx Table 1. Demography and baseline characteristics of study population Table2.xlsx Table 2. Comparison of Lipid profile of study population at week 1, 2, 4, & 12 and serum ApoA1, ApoE & PCSK9 levels at week 0 & 12 (Mean±SD) Legend: ApoA1: Apolipoprotein A1 ApoE: Apolipoprotein E HDL-C: High density lipoprotein cholesterol LDL-C: Low density lipoprotein cholesterol PCSK9: Proprotein convertase subtilisin/kexin type 9 SD: Standard deviation TC: Total cholesterol TG: Triglyceride Table3.xlsx Table 3. Mean change of Lipid profile of study population at week 1, 2, 4, & 12 and serum ApoA1, ApoE & PCSK9 levels at week 12 from the baseline (Mean±SD) Legend: ApoA1: Apolipoprotein A1 ApoE: Apolipoprotein E HDL-C: High density lipoprotein cholesterol LDL-C: Low density lipoprotein cholesterol PCSK9: Proprotein convertase subtilisin/kexin type 9 SD: Standard deviation TC: Total cholesterol TG: Triglyceride Table4.xlsx Table 4. Genotype frequency and allelic frequency of SNPs of ApoA1, ApoE & PCSK9 Legend: ApoA1: Apolipoprotein A1 ApoE: Apolipoprotein E PCSK9: Proprotein convertase subtilisin/kexin type 9 SNP: Single nucleotide polymorphism Table5.xlsx Table 5. Genetic-phenotypic association of mean change in LDL-C at follow-up intervals with studied SNPs Legend: ApoA1: Apolipoprotein A1 ApoE: Apolipoprotein E LDL-C: Low density lipoprotein cholesterol NR: Normal response PCSK9: Proprotein convertase subtilisin/kexin type 9 SR: Slow response Supplementary.docx Supplementary file Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8727328","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":594272744,"identity":"6031a0ff-6e49-4980-b6f8-0f9e2dbbeec0","order_by":0,"name":"Harmeet Rehan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYBACAzhLAog/NoBYjI0HiNBiANbCOLMBTDUQr4WZF6yFgQGvFnP2s083fKj4k88v3fzsse0Omzrd9sNAW2psonFpsexJN7s544yB5cw5x8yNc8+kSZidSQRqOZaW24DLYQfS2G7zthkYGNxIMJPObTssYXYAqIWx4TBuLeefsd3++8/AwP5G+jdpS5CW8w8JaLkBtIWxAWiLRI6ZNCNIyw1Cttx4xnaz55ixgcSNnDLJ3rY0yW03gLYk4PPL+TS2Gz9q5Az4Z6Rvk/jZZsNvdj794YMPNTY4teAACaQpHwWjYBSMglGABgAG2WKOl0nzUgAAAABJRU5ErkJggg==","orcid":"","institution":"Lady Hardinge Medical College, University of Delhi, India","correspondingAuthor":true,"prefix":"","firstName":"Harmeet","middleName":"","lastName":"Rehan","suffix":""},{"id":594272745,"identity":"bb43d8ad-3af1-4d0c-a2a7-770dd027b654","order_by":1,"name":"Aman Singh","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Aman","middleName":"","lastName":"Singh","suffix":""},{"id":594272746,"identity":"8d182fb9-77c5-40db-9052-4389d45373e9","order_by":2,"name":"Lalit Gupta","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lalit","middleName":"","lastName":"Gupta","suffix":""},{"id":594272747,"identity":"a7b8509d-d06c-4ef7-9ba3-ef35eee73b11","order_by":3,"name":"Madhur Yadav","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Madhur","middleName":"","lastName":"Yadav","suffix":""}],"badges":[],"createdAt":"2026-01-29 05:26:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8727328/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8727328/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103400589,"identity":"76500edf-a29d-4e02-820c-974aa4ebfe56","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":310824,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of genotyping procedure\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eDNA: Deoxyribonucleic acid\u003c/p\u003e\n\u003cp\u003ePCR: Polymerase chain reaction\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/29ea2627612a399ab1ea2a78.jpg"},{"id":103400597,"identity":"8ab436ec-ea9d-4a0b-800f-7109eb062712","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":417580,"visible":true,"origin":"","legend":"\u003cp\u003eConsort diagram of the study\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eApoA1: Apolipoprotein A1\u003c/p\u003e\n\u003cp\u003eApoE: Apolipoprotein E\u003c/p\u003e\n\u003cp\u003eEDTA: Ethylenediaminetetraacetic acid\u003c/p\u003e\n\u003cp\u003eLLD: Lipid lowering drug\u003c/p\u003e\n\u003cp\u003ePCSK9: Proprotein convertase subtilisin/kexin type 9\u003c/p\u003e\n\u003cp\u003eT2DM: Type 2 diabetes mellitus\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/cd5ad4b5b9659fb9e26d90e8.jpg"},{"id":103400605,"identity":"a5192552-8431-418f-b8cf-94e838c407fc","added_by":"auto","created_at":"2026-02-25 09:23:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":267168,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of mean lipid profile levels of study population at week 0, 1, 2, 4 and 12\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eHDL-C: High density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eLDL-C: Low density lipoprotein cholesterol\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/21dbea6e0eba50e21e8eb6ec.jpg"},{"id":106094560,"identity":"dab7f334-c248-4509-afbd-db605e5a1384","added_by":"auto","created_at":"2026-04-03 11:42:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1433626,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/ce849aed-a311-4d40-bdd8-6ef3267b40d0.pdf"},{"id":103507259,"identity":"c0debf30-e561-4e31-b32c-d3d1c93b84d3","added_by":"auto","created_at":"2026-02-26 13:40:49","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10744,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Demography and baseline characteristics of study population\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/1e89e2d50702de4b013ae7cc.xlsx"},{"id":103400601,"identity":"9b24159e-ed9f-4f21-b13f-714b4019a78b","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11082,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2. Comparison of Lipid profile of study population at week 1, 2, 4, \u0026amp; 12 and serum ApoA1, ApoE \u0026amp; PCSK9 levels at week 0 \u0026amp; 12 (Mean±SD)\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eApoA1: Apolipoprotein A1\u003c/p\u003e\n\u003cp\u003eApoE: Apolipoprotein E\u003c/p\u003e\n\u003cp\u003eHDL-C: High density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eLDL-C: Low density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003ePCSK9: Proprotein convertase subtilisin/kexin type 9\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e\n\u003cp\u003eTC: Total cholesterol\u003c/p\u003e\n\u003cp\u003eTG: Triglyceride\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/ee4b6e7389c856cc3951a292.xlsx"},{"id":103400591,"identity":"69e9f8c1-bf70-4465-9f91-84b7dee1d6f4","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10775,"visible":true,"origin":"","legend":"\u003cp\u003eTable 3. Mean change of Lipid profile of study population at week 1, 2, 4, \u0026amp; 12 and serum ApoA1, ApoE \u0026amp; PCSK9 levels at week 12 from the baseline (Mean±SD)\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eApoA1: Apolipoprotein A1\u003c/p\u003e\n\u003cp\u003eApoE: Apolipoprotein E\u003c/p\u003e\n\u003cp\u003eHDL-C: High density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eLDL-C: Low density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003ePCSK9: Proprotein convertase subtilisin/kexin type 9\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e\n\u003cp\u003eTC: Total cholesterol\u003c/p\u003e\n\u003cp\u003eTG: Triglyceride\u003c/p\u003e","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/9698c156f80f9aea7e164c3a.xlsx"},{"id":103400592,"identity":"2d663a60-a17d-4551-9cdc-313db30bf11c","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":10350,"visible":true,"origin":"","legend":"\u003cp\u003eTable 4. Genotype frequency and allelic frequency of SNPs of ApoA1, ApoE \u0026amp; PCSK9\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eApoA1: Apolipoprotein A1\u003c/p\u003e\n\u003cp\u003eApoE: Apolipoprotein E\u003c/p\u003e\n\u003cp\u003ePCSK9: Proprotein convertase subtilisin/kexin type 9\u003c/p\u003e\n\u003cp\u003eSNP: Single nucleotide polymorphism\u003c/p\u003e","description":"","filename":"Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/5eb820aac7752bf736c60f2e.xlsx"},{"id":103507270,"identity":"85c640ce-0e3d-410a-87c7-256951ed50c1","added_by":"auto","created_at":"2026-02-26 13:40:51","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":12582,"visible":true,"origin":"","legend":"\u003cp\u003eTable 5. Genetic-phenotypic association of mean change in LDL-C at follow-up intervals with studied SNPs\u003c/p\u003e\n\u003cp\u003eLegend:\u003c/p\u003e\n\u003cp\u003eApoA1: Apolipoprotein A1\u003c/p\u003e\n\u003cp\u003eApoE: Apolipoprotein E\u003c/p\u003e\n\u003cp\u003eLDL-C: Low density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eNR: Normal response\u003c/p\u003e\n\u003cp\u003ePCSK9: Proprotein convertase subtilisin/kexin type 9\u003c/p\u003e\n\u003cp\u003eSR: Slow response\u003c/p\u003e","description":"","filename":"Table5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/2f0cc2840569efaa21460920.xlsx"},{"id":103400593,"identity":"4ef21b86-0985-4f5d-9d68-db79cb29d823","added_by":"auto","created_at":"2026-02-25 09:23:09","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":19456,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary file\u003c/p\u003e","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8727328/v1/4e49a07628d6cc69898a48d0.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Association of polymorphisms of ApoE, ApoA1, PCSK9 with LDL-C modification following Atorvastatin therapy in dyslipidemic patients.","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe deaths due to non-communicable diseases (NCDs) are on the rise and account for 74% of all deaths worldwide, with 41.6% of such deaths due to cardiovascular diseases (CVD) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The prevalence of atherosclerotic cardiovascular disease (ASCVD) has declined in Western countries in the last two decades whereas amongst South Asians, it has increased. The multiple factors contributing to this rise are; metabolic syndrome (viz. dyslipidemia, hypertension, obesity, impaired glucose tolerance), sedentary lifestyles, unhealthy diets \u0026amp; habits including excess salt intake, alcohol, tobacco, urbanization, lower socio-economic status, potentially air pollution etc. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), making the Asians prone to develop ASCVD a decade earlier with a malignant course (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The result of which, more than half of CAD-related deaths in India occur before 50 years of age, and 25% of myocardial infarctions (MI) befall before 40 years of age (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eApo Lipoprotein A1 (ApoA1), Apo Lipoprotein E (ApoE) and Proprotein convertase subtilisin/kexin type 9 (PCSK9) play important role in metabolism of lipids, consequently, changes in their serum concentration contributes to development of ASCVD (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong these risk factors for the development of ASCVD dyslipidemia is preventable. It is characterized by abnormal circulating lipid [elevation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and a decrease in the high-density lipoprotein cholesterol (HDL-C)]. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Nearly three-fourths of the adult Indian population has been reported to have dyslipidemia; hence, the primordial prevention and treatment of dyslipidemia may play a crucial role in reducing the burden of ASCVD (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe management of dyslipidemia is based on risk stratification of patients using various risk calculators (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The therapy of dyslipidemia includes a combination of therapeutic lifestyle modifications and lipid-modifying drugs (LMD) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The goal of the therapy is to reduce LDL-C by \u0026ge;\u0026thinsp;50% (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The use of statins remains the cornerstone both for the treatment of dyslipidemia and the prevention of ASCVD (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Though inter-individual variations in the lipid-modifying response of statins are evident, their cause has not been firmly established (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The distinct genetic makeup of the South Asian population may be one of the non-modifiable factors responsible for the early development of ASCVD. Whole genome sequencing and genome-wide association studies (GWAS) have identified various polymorphisms of genes related to lipid metabolism and transport, affecting the circulating lipid and lipoprotein levels (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Detectable mutations in \u003cem\u003eApoA1\u003c/em\u003e, \u003cem\u003eApoE\u003c/em\u003e, \u003cem\u003ePCSK9\u003c/em\u003e, and other genes contribute to the development of dyslipidemia (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Analysis of these genetic variations may be useful for early diagnosis and treatment of dyslipidemia (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Therefore, to optimize the benefit of statins, the present study was conducted to identify polymorphisms in \u003cem\u003eApoA1\u003c/em\u003e, \u003cem\u003eApoE\u003c/em\u003e, and \u003cem\u003ePCSK9\u003c/em\u003e genes and find their association with variation in lipid-modifying response of patients.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cp\u003eA prospective observational study was conducted on 61 treatment-naive dyslipidemic patients older than eighteen years of age prescribed high-intensity statins. Dyslipidemia was defined as patients having either raised serum LDL-C level [\u0026gt;\u0026thinsp;100 mg/dL (for people with CVD risk factors)], TC [\u0026ge;\u0026thinsp;200 mg/dL] and TG (\u0026gt;\u0026thinsp;200 mg/dL) and low HDL-C levels (\u0026lt;\u0026thinsp;40 mg/dL for males; \u0026lt;50 mg/dL for females) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Patients with history of diabetes mellitus (HbA1c\u0026thinsp;\u0026gt;\u0026thinsp;6.5), hypothyroidism, lipodystrophy, polycystic ovarian syndrome, chronic kidney disease, fatty liver, cholestasis, alcohol consumption, pregnancy, post organ transplant patients on immunosuppressants were excluded from the study.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and after prior approval from the Institutional Ethical Committee, Lady Hardinge Medical College, (LHMC/IEC) and obtaining written informed consent from all the participants. Any treatment-associated adverse events observed/reported during the study were documented in the Suspected Adverse Drug Reaction Reporting Form.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003eAt baseline, a fasting venous blood sample (5ml) was withdrawn under all aseptic precautions, 4ml of blood was used to estimate lipid profile (TC, LDL-C, HDL-C, TG) using an autoanalyzer and ApoA1, PCSK9 \u0026amp; ApoE levels by sandwich Enzyme-linked immunosorbent assay (ELISA) method. ELISA kits for human serum ApoA1, PCSK9 \u0026amp; ApoE were procured from Shanghai Coon Koon Biotech, and the assay was conducted according to the manufacturer\u0026rsquo;s instruction manual. The remaining 1ml of blood sample was used for deoxyribonucleic acid (DNA) extraction and genotyping of candidate genes (\u003cem\u003eAPOA1, PCSK9\u003c/em\u003e \u0026amp; \u003cem\u003eAPOE\u003c/em\u003e) by SNaPshot\u003csup\u003e\u0026reg;\u003c/sup\u003e method (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003ePatients were followed -up at 1, 2, 4, and 12 weeks of initiation of LLM for refill of the prescription, estimation of lipid profile, and monitoring of ADR, if any. Additionally, at the 12-week follow-up, the estimation of serum ApoA1, PCSK9 \u0026amp; ApoE was repeated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe responsiveness of patients to statin therapy was considered normal (NR) if the reduction in LDL-C was more than or equal to 50% from the baseline value, whereas LDL-C levels achieved\u0026thinsp;\u0026lt;\u0026thinsp;50% were regarded as slow response (SR) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe biochemical parameters have been presented as mean and standard deviation. The change in lipid profile following statin therapy is presented as a percentage change. The significance of lipid profile change from baseline was calculated using paired t-test. To find the association of genetic polymorphism with percentage change in lipid profile was assessed using one-tailed \u0026amp; two-tailed Fisher\u0026rsquo;s exact test, where two and three variants of SNP were detected, respectively. p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eOut of 65 dyslipidemic patients screened, 61 were enrolled in the study. During the intervention, six patients were lost to follow-up (Fig.\u0026nbsp;2). The data of 55 patients is presented.\u003c/p\u003e\n\u003ch3\u003eDemography\u003c/h3\u003e\n\u003cp\u003eOut of the 55 patients, 29 (52.7%) were males and 26 (47.3%) were females. The patients were on average 44.31\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7 years old, weighing 74.97\u0026thinsp;\u0026plusmn;\u0026thinsp;8.77 kgs. The mean dose of atorvastatin used was 44.36 mg, with atorvastatin 80 mg used by 8 patients and atorvastatin 40 mg used by 47 (85.45%) patients (Table\u0026nbsp;1).\u003c/p\u003e\n\u003ch3\u003eBiochemical Parameters\u003c/h3\u003e\n\u003cp\u003eOverall LDL-C values decreased from 176.22\u0026thinsp;\u0026plusmn;\u0026thinsp;43.84 mg/dL at baseline to 78.64\u0026thinsp;\u0026plusmn;\u0026thinsp;19.26 mg/dL at 12 weeks (54.55% decrease). The reduction in total cholesterol values was 40.6% at the end of follow-up from 265.47\u0026thinsp;\u0026plusmn;\u0026thinsp;80.21 mg/dL at baseline to 151.98\u0026thinsp;\u0026plusmn;\u0026thinsp;20.71 mg/dL at 12 weeks. HDL-C levels showed a gradual increase over time from 43.55\u0026thinsp;\u0026plusmn;\u0026thinsp;9.52 mg/dL at baseline to 47.18\u0026thinsp;\u0026plusmn;\u0026thinsp;10.15 at 12 weeks (8.76% increase). Triglyceride values decreased from 261.96\u0026thinsp;\u0026plusmn;\u0026thinsp;192.70 mg/dL at baseline to 109.65\u0026thinsp;\u0026plusmn;\u0026thinsp;41.13 mg/dL at 12 weeks (53.1% decrease). The mean baseline value of ApoA1 was 123.61\u0026thinsp;\u0026plusmn;\u0026thinsp;30.61 ng/mL, which increased to 142.95\u0026thinsp;\u0026plusmn;\u0026thinsp;30.92 ng/mL at 12 weeks (17.29% increase). The values of ApoE decrease from 56.51\u0026thinsp;\u0026plusmn;\u0026thinsp;15.02 ng/mL at baseline to 32.58\u0026thinsp;\u0026plusmn;\u0026thinsp;6.99 ng/mL at 12 weeks (40.46% decrease). Levels of PCSK9 increased by 12.35% from 403.25\u0026thinsp;\u0026plusmn;\u0026thinsp;117.86 ng/mL at baseline to 450.86\u0026thinsp;\u0026plusmn;\u0026thinsp;127.99 ng/mL at 12 weeks. The change in all lipid profile parameters was significant, beginning from the baseline and continuing until the end of the follow-up (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). No significant difference in lipid profile levels was seen between males and females (Table\u0026nbsp;2 and Table\u0026nbsp;3). Decrease in LDL-C, TC, TG \u0026amp; PCSK9 was 56.14%, 45.12%, 54.01% \u0026amp; 45.84% following atorvastatin 80 mg therapy, respectively, whereas with atorvastatin 40 mg the decrease was 54.28%, 39.83%, 52.95% \u0026amp; 39.54% respectively. HDL-C levels increased (11.18% vs 8.35%) more with atorvastatin 80 mg compared to 40 mg. Levels of ApoA1 \u0026amp; PCSK9 increased by 25.81% \u0026amp; 10.31% respectively, and ApoE decreased by 45.84% with atorvastatin 80 mg, whereas with atorvastatin 40mg, increases in ApoA1 \u0026amp; PCSK9 were 15.84% \u0026amp; 12.69%, respectively, and the decrease in ApoE was 39.54%. Results of mean percentage change in the lipid profile parameters at different intervals are provided in the supplementary data.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cb\u003eGenetic Analysis\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eI. Genotype frequency\u003c/h2\u003e \u003cp\u003eOf the total 55 dyslipidemic patients that were analyzed, genetic analysis revealed that for SNPs of \u003cem\u003eApoA1\u003c/em\u003e under study, rs5069(G\u0026thinsp;\u0026gt;\u0026thinsp;A) was observed in 41 patients and rs1799837(C\u0026thinsp;\u0026gt;\u0026thinsp;T) was observed in 48 patients, for SNPs of \u003cem\u003eApoE\u003c/em\u003e, rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) was observed in 50 patients and rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) was observed in 52 patients, for SNPs of \u003cem\u003ePCSK9\u003c/em\u003e, rs505151(G\u0026thinsp;\u0026gt;\u0026thinsp;A) was observed in 53 patients and rs11591147(G\u0026thinsp;\u0026gt;\u0026thinsp;T) was observed in 55 patients.\u003c/p\u003e \u003cp\u003eThe frequency of variants \u003cem\u003eGG\u003c/em\u003e, \u003cem\u003eGA\u003c/em\u003e, and \u003cem\u003eAA\u003c/em\u003e of rs5069(G\u0026thinsp;\u0026gt;\u0026thinsp;A) of \u003cem\u003eApoA1\u003c/em\u003e was 97.56%, 2.44%, and 0% respectively. For the \u003cem\u003eApoA1\u003c/em\u003e rs1799837(C\u0026thinsp;\u0026gt;\u0026thinsp;T), only the \u003cem\u003eCC\u003c/em\u003e variant was observed in all 48 patients. The variants of \u003cem\u003eApoE\u003c/em\u003e rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) were observed at a frequency of 98% for \u003cem\u003eCC\u003c/em\u003e, 2% for \u003cem\u003eCT\u003c/em\u003e, and 0% for \u003cem\u003eTT\u003c/em\u003e (Table\u0026nbsp;4). \u003cem\u003eTT\u003c/em\u003e and \u003cem\u003eTC\u003c/em\u003e variants were observed for \u003cem\u003eApoE\u003c/em\u003e rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) SNP with frequencies of 96.15% and 3.85% respectively. The frequency of \u003cem\u003eGG\u003c/em\u003e, \u003cem\u003eGA\u003c/em\u003e, and \u003cem\u003eAA\u003c/em\u003e variants of \u003cem\u003ePCSK9\u003c/em\u003e rs505151(G\u0026thinsp;\u0026gt;\u0026thinsp;A) was 1.89%, 16.89%, and 81.13% respectively. For the \u003cem\u003ePCSK9\u003c/em\u003e rs11591147(G\u0026thinsp;\u0026gt;\u0026thinsp;T) SNP, all 55 patients had the \u003cem\u003eGG\u003c/em\u003e variant (Table\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eFor rs5069(G\u0026thinsp;\u0026gt;\u0026thinsp;A), the reference \u003cem\u003eG\u003c/em\u003e allele was observed in 98.79% of samples, and the mutant \u003cem\u003eA\u003c/em\u003e allele was observed in 1.21% of samples. The \u003cem\u003eC\u003c/em\u003e allele was the only one observed for rs1799837(C\u0026thinsp;\u0026gt;\u0026thinsp;T). For rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T), the \u003cem\u003eC\u003c/em\u003e allele was predominant (99%), with the \u003cem\u003eT\u003c/em\u003e allele present in only 1% samples. Similarly, the reference \u003cem\u003eT\u003c/em\u003e allele was predominant (98.02%) for rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) as compared to the mutant \u003cem\u003eC\u003c/em\u003e allele (1.92%). Contrastingly, for rs505151(G\u0026thinsp;\u0026gt;\u0026thinsp;A), the mutant allele \u003cem\u003eA\u003c/em\u003e was observed in 89.62% samples while reference allele \u003cem\u003eG\u003c/em\u003e was observed in 10.38% of samples. For rs11591147(G\u0026thinsp;\u0026gt;\u0026thinsp;T), all the samples had the reference \u003cem\u003eG\u003c/em\u003e allele.\u003c/p\u003e \u003cp\u003e \u003cb\u003eII Genetic-phenotypic association\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eWhen comparing response categories in LDL-C with variants of SNPs, variants of rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) of \u003cem\u003eApoE\u003c/em\u003e showed a statistically significant association with LDL-C reduction (\u0026gt;\u0026thinsp;50%) from baseline to week 12 (p\u0026thinsp;=\u0026thinsp;0.05). The combined LDL-C lowering effect of SNPs of ApoE [rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) \u0026amp; rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C)] showed association (p\u0026thinsp;=\u0026thinsp;0.13) with response categories of LDL-C from baseline to week 12; similarly, a combination of SNPs which had more than one observed variant, showed association with LDL-C reduction categories (p\u0026thinsp;=\u0026thinsp;0.18) at week 12. At other intervals the response categories of LDL-C either had no association or the associations were not significant (Table\u0026nbsp;5).\u003c/p\u003e "},{"header":"DISCUSSION","content":"\u003cp\u003eDyslipidemia, characterized by elevated levels of lipids in the blood, is substantially affected by non-modifiable risk factors, specifically the defects in genes encoding for lipoproteins (e.g., ApoE, ApoA1), enzymes (e.g., PCSK9), and proteins involved in lipid metabolism and transport. Genome-wide association studies (GWAS) have identified hundreds of SNPs associated with lipid traits, each exerting a modest effect, but collectively contributing significantly to the risk of dyslipidemia. Understanding the genetic nature of dyslipidemia is crucial for developing personalized interventions, as individuals may carry unique combinations of genetic variants that influence their lipid levels and response to statin therapy (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Genetic screening for risk alleles could allow identification of individuals at higher risk for dyslipidemia, enabling earlier interventions tailored to their specific genetic makeup. This knowledge could guide the development of targeted therapies, potentially improving treatment efficacy and hence reducing the risk of major cardiovascular events (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, the mean percentage reduction of LDL-C at week 1 from the baseline value was \u0026shy;23.15\u0026thinsp;\u0026plusmn;\u0026thinsp;9.25%, which further reduced by \u0026shy;34.01\u0026thinsp;\u0026plusmn;\u0026thinsp;9.63%, \u0026shy;44.48\u0026thinsp;\u0026plusmn;\u0026thinsp;11.13% and \u0026shy;54.55\u0026thinsp;\u0026plusmn;\u0026thinsp;7.88% at the end of 2, 4 \u0026amp; 12 weeks of atorvastatin therapy, respectively. Furthermore, atorvastatin 80 mg reduced LDL-C by 25.55% by week one, which increased to 56.14% reduction by week 12, whereas atorvastatin 40 mg reduced LDL-C by 22.74% which reached a reduction of 54.28% by week 12. A randomized, double-blind study conducted in USA by Nohria A, et al. showed that in atherosclerotic patients, atorvastatin 10 mg and 80 mg reduced LDL-C by 13% \u0026amp; 36% after 1 week, 27% \u0026amp; 44% after 2 weeks, and 36% \u0026amp; 50% after 4 weeks, respectively (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Similarly, the JUPITER trial revealed that high-intensity statins reduced LDL-C by more than 50% (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Further, in our study, the mean percentage change from baseline for TC was \u0026minus;\u0026thinsp;15.76\u0026thinsp;\u0026plusmn;\u0026thinsp;9.92% at week one, -24.77\u0026thinsp;\u0026plusmn;\u0026thinsp;11.97% at week two, -33.75\u0026thinsp;\u0026plusmn;\u0026thinsp;11.60% at week four, and \u0026minus;\u0026thinsp;40.60\u0026thinsp;\u0026plusmn;\u0026thinsp;9.24% at week 12. Atorvastain 80 mg led to a decrease of 25.55% after one week and the reduction was 56.14% by week 12, whereas atorvastatin 40 mg led to 22.74% by week one and 54.28% by week 12. Similarly, patients in the Nohria A, et al., study had TC reduction of 10% \u0026amp; 30% after week 1, 21% \u0026amp; 35% after week 2, 21% \u0026amp; 36% after week 3 of atorvastatin 10 mg and atorvastatin 80 mg therapy, respectively (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The lipid lowering capacity of atorvastatin in our study suggested that its clinical benefits translated as early as after 1 week of therapy. Nohria A, et al., also reported decrease in TC throughout the follow up, but the percentage fall was lesser than LDL-C (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The reduction in LDL-C and TC plateaued after 4 weeks and the difference in LDL-C reduction between atorvastatin 80 mg and 40 mg converged at longer intervals. In our study the mean percentage change from baseline for HDL-C was +\u0026thinsp;3.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.94% at week one, +\u0026thinsp;6.26\u0026thinsp;\u0026plusmn;\u0026thinsp;6.67% at week two, +\u0026thinsp;7.98\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2% at week four, +\u0026thinsp;8.76\u0026thinsp;\u0026plusmn;\u0026thinsp;9.63% at week 12 and the mean percentage change from baseline for TG was \u0026minus;\u0026thinsp;22.67\u0026thinsp;\u0026plusmn;\u0026thinsp;14.01 week one, -35.65\u0026thinsp;\u0026plusmn;\u0026thinsp;13.27% at week two, -46.28\u0026thinsp;\u0026plusmn;\u0026thinsp;17.23% at week four, -53.10\u0026thinsp;\u0026plusmn;\u0026thinsp;16.75 at week 12. The CURVES study reported, HDL-C increase by atorvastatin 40 mg at week 8 as +\u0026thinsp;4.8% and the TG decrease by atorvastatin 40 mg at week 8 as -32% (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), while a study by Helmut G. Schrott, et al., reported HDL-C increase as +\u0026thinsp;2% at day 14 and TG decrease as -14% at day 7 and \u0026minus;\u0026thinsp;24% at day 14 of atorvastatin therapy (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The mean percentage HDL-C increase and the TG decrease was relatively more in our study (Supplementary file).\u003c/p\u003e \u003cp\u003eThe mean change from baseline for ApoA1 at week twelve was +\u0026thinsp;17.29\u0026thinsp;\u0026plusmn;\u0026thinsp;13.19%. Contrastingly, a meta-analysis demonstrated variable change in ApoA1 levels with statin therapy, ranging from \u0026minus;\u0026thinsp;5.1% to +\u0026thinsp;6.7%. (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Comparatively, Rostam Yazdani, et al., demonstrated that aerobic exercise led to a significant increase in ApoA1 levels (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), offering a potential explanation for higher rise in serum ApoA1 levels in our study. Further as discussed previously, our study had higher increase in HDL-C and ApoA1 levels after atorvastatin therapy. Since, ApoA1 is a principal apolipoprotein component in HDL-C, and has considerable association with HDL-C (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Offering a possible explanation for the higher ApoA1 increase seen in our study. A meta-analysis to study the association of HDL-C \u0026amp; ApoA1 levels with ASCVD risk outcome in patients on statin revealed a strong association. Whereas, the increase in ApoA1 levels was associated with decreased risk of CVD events but the association was not evident with the increase in HDL-C levels (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In our study, the mean percentage reduction of ApoE levels after 12 weeks of atorvastatin therapy was \u0026minus;\u0026thinsp;40.46\u0026thinsp;\u0026plusmn;\u0026thinsp;12.30%. Similarly, Ngoc-Anh Le, et al., demonstrated serum ApoE levels decrease at week four by 37% and 49% by atorvastatin 20mg and 80 mg respectively (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). ApoE facilitates reverse cholesterol transport from peripheral tissues to liver. The majority of ApoE in serum is derived from hepatocytes, whereas macrophage-specific expression of ApoE is atheroprotective (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Paradoxically, patients with normal HDL-C with low serum ApoE levels had lower incidence of cardiovascular events compared to patients who had high ApoE with normal HDL-C levels (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Suggesting a complex relationship of ApoE levels with CVD requiring further investigation (Supplementary file).\u003c/p\u003e \u003cp\u003eIndians are at a higher risk to develop severe intensity of serious ASCVD with interindividual variation in responsiveness to statin (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), but a sub study of ASCOT-LLA trial by Chapman N, et al., showed no significant difference in reduction of LDL-C (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e),(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and TC (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) between Whites and South Asians. Gupta M, et al., demonstrated that atorvastatin treatment for the same duration and dose produced higher increase in HDL-C and more decrease in TG levels in South Asian population compared to White population (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The higher increase in HDL-C levels (+\u0026thinsp;8.76\u0026thinsp;\u0026plusmn;\u0026thinsp;9.63%) and more decrease in TG levels (-53.10\u0026thinsp;\u0026plusmn;\u0026thinsp;16.75) in our study population could be due to dietary and genetic factors playing role in variation in two sets of population and individuals (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe genetic analysis of blood samples in our study revealed a significant association (p\u0026thinsp;=\u0026thinsp;0.05) between LDL-C reduction by atorvastatin therapy after 12 weeks and variants of rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) of \u003cem\u003eApoE\u003c/em\u003e. In our literature search, no study was available that studied the effect of rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) on atorvastatin-mediated LDL-C reduction. Analysis for variants of rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) of \u003cem\u003eApoE\u003c/em\u003e also did not show association with LDL-C reduction following atorvastatin therapy. Contrastingly, a GWAS by Chasman D. I, et al., showed a genome-wide level significance of LDL-C reduction by rosuvastatin due to rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Combination of variants of rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T) \u0026amp; rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) were associated with a reduction in LDL-C after 12 weeks of atorvastatin therapy (p\u0026thinsp;=\u0026thinsp;0.13). Similarly, Lei Zhang, et al., showed better statin lipid-lowering response in patients having \u003cem\u003ee2\u003c/em\u003e phenotype. The association of combination of variants of rs7412(C\u0026thinsp;\u0026gt;\u0026thinsp;T), rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C)], rs5069(G\u0026thinsp;\u0026gt;\u0026thinsp;A) \u0026amp; rs505151(G\u0026thinsp;\u0026gt;\u0026thinsp;A) with LDL-C reduction was visible but non-significant (p\u0026thinsp;=\u0026thinsp;0.18) (Table\u0026nbsp;5).\u003c/p\u003e \u003cp\u003eIn our study the mean percentage change in serum PCSK9 levels from baseline after twelve weeks of statin therapy was +\u0026thinsp;12.35\u0026thinsp;\u0026plusmn;\u0026thinsp;7.52% (Table\u0026nbsp;5.3) with a rise of 47.61 ng/mL. Similarly, in a meta-analysis A. Sahebkar, et al., also demonstrated mean increase of 40.72 ng/mL in serum PCSK9 levels in patients treated with statins (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), which was lower than our study.\u003c/p\u003e \u003cp\u003eOur results demonstrated LDL-C lowering effect of atorvastatin which was evident after week 1 (\u0026shy;23\u0026thinsp;\u0026plusmn;\u0026thinsp;9.25%,) and later showcased the time dependent lipid lowering effect until at week 12 (\u0026shy;54.55%) (Table\u0026nbsp;5). The increased serum ApoA1 and PCSK9 levels, and decreased ApoE levels after atorvastatin therapy observed in the study may benefit ASCVD patients. A significant association of rs429358(T\u0026thinsp;\u0026gt;\u0026thinsp;C) SNPs \u003cem\u003eApoE\u003c/em\u003e could help in personalizing the treatment of dyslipidemia. The genetic mapping of genes associated with dyslipidemia to find patients\u0026rsquo; responsiveness to statins which may improve statins\u0026rsquo; preventive and therapeutic effect in CVD.\u003c/p\u003e"},{"header":"CONCLUSIUON","content":"\u003cp\u003eThe study demonstrated that atorvastatin therapy effectively reduced LDL-C, TC, and TG while it increased HDL-C levels in dyslipidemia patients. Additionally, atorvastatin increased serum ApoA1 and PCSK9 levels, and decreased ApoE levels after 12 weeks, translating its benefit to ASCVD patients. The observed percentage changes in lipid profile parameters were significantly associated with \u003cem\u003eApoE\u003c/em\u003e (rs429358), highlighting the influence of genetic variants on the responsiveness of patients to statin therapy. To improve outcomes of statin therapy, incorporation of genetic screening in patient treatment plan may have a vital role in preventive and treating dyslipidemias amongst Indians. Further investigation in larger studies may shed more light on these associations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe greatly appreciate the contribution of Dr. Mohammed Faruq, Senior Principal Scientist, CSIR-Institute of Genomics and Integrative Biology, for providing his expertise towards the genetic analysis of the samples.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOriginal data may be made available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNoncommunicable diseases [Internet]. [cited 2024 Aug 28]. 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Diabetes Obes Metab. 2015;17(11):1042\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), lipid profile, statin, genetic variation, single nucleotide polymorphism","lastPublishedDoi":"10.21203/rs.3.rs-8727328/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8727328/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Dyslipidemia, a risk factor for atherosclerotic cardiovascular disease, is primarily managed by statins. Single-nucleotide polymorphisms (SNPs) may influence LDL-C reduction variability seen with statins. Treatment-naïve adult dyslipidemic patients prescribed Atorvastatin (40/80mg) were enrolled in a 12-week observational study. Lipid profiles were estimated at baseline \u0026 follow-up (week 1, 2, 4, 12), serum ApoA1, ApoE \u0026 PCSK9 were estimated at baseline and week 12. Six SNPs were genotyped at baseline. LDL-C reduction of ≥50% was compared with SNP variants. In 55 patients who completed follow-up, a decrease in LDL-C, total cholesterol, triglycerides, and ApoE was 54.55%, 40.60%, 53.1%, and 40.46%, respectively. Meanwhile, HDL-C, ApoA1 \u0026 PCSK9 levels increased by 8.76%, 17.29% \u002612.35% respectively. Reduction in LDL-C levels was associated with variants of rs429358(T\u003eC) [p= 0.05], rs7412(C\u003eT) \u0026 rs429358(T\u003eC) combined [p= 0.13], and rs7412(C\u003eT), rs429358(T\u003eC), rs5069(G\u003eA) \u0026 rs505151(G\u003eA) combined [p= 0.18]. Genotype-based therapy may improve treatment outcomes for atorvastatin in dyslipidemia.","manuscriptTitle":"Association of polymorphisms of ApoE, ApoA1, PCSK9 with LDL-C modification following Atorvastatin therapy in dyslipidemic patients.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-25 09:22:58","doi":"10.21203/rs.3.rs-8727328/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"adca5e77-e381-4373-bb0c-92e4ff4812ea","owner":[],"postedDate":"February 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63242238,"name":"Health sciences/Health care/Therapeutics"},{"id":63242239,"name":"Biological sciences/Genetics/Medical genetics"}],"tags":[],"updatedAt":"2026-04-02T15:35:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-25 09:22:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8727328","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8727328","identity":"rs-8727328","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}