تأثير تعدد أشكال جين PCSK9 في فعالية عقار الأتورفاستاتين في عينة من مرضى ارتفاع شحميات الدم العراقيين

Impact of PCSK9 Gene Polymorphism on Atorvastatin Efficacy in a sample of Iraqi Hyperlipidemic Patients

Abstract
Background: Hyperlipidemia, a disease characterized by elevated lipid levels in the blood, significantly increases the risk of atherosclerosis and cardiovascular diseases, particularly coronary heart disease. Clinical observations have shown that many hyperlipidemic patients continue to experience high blood cholesterol and low-density lipoprotein levels despite treatment with lipid lowering drugs like atorvastatin, a common statin used to decrease blood cholesterol levels. Proprotein convertase subtilisin/kexin type 9 plays an important role in the regulation of low-density lipoprotein metabolism via its effect on low-density lipoprotein receptor recycling. Genetic variations within the Proprotein convertase subtilisin/kexin type 9 gene (particularly rs28942111; T>A SNP) which is one of gain of function mutation which result in increasing the effect of Proprotein convertase subtilisin/kexin type 9 that may influence the therapeutic response to atorvastatin in lowering plasma cholesterol.
Aim of study: This study aims to investigate the impact of the Proprotein convertase subtilisin/kexin type 9 rs28942111; T>A SNP on the cholesterol lowering response to atorvastatin among sample of Iraqi patients diagnosed with primary hyperlipidemia. Additionally, it evaluates lipid profile parameters and atherogenic indices, including the Atherogenic Index of Plasma and Castelli Risk Indices I and II.
Methodology: A cross-sectional study was conducted involving 149 Iraqi patients aged between 28 and 85 years, all of whom were diagnosed with primary hyperlipidemia and had been taking a daily oral dose of 40 mg atorvastatin for a minimum six months. Lipid profile, liver function tests, and atherogenic indices (Atherogenic Index of Plasma and Castelli Risk Indices I and II) were assessed. Genotyping of the Proprotein convertase subtilisin/kexin type 9 rs28942111; T>A SNP was performed using allele-specific PCR.
Results: Among the 149 patients, 85.9% were TT allele carriers (the homozygous wild type) and 14.1% were AA allele carriers (the homozygous mutant type) of the rs28942111; T>A SNP. No heterozygous mutant type was detected (TA). AA allele carriers exhibited significantly higher levels of Low-density lipoprotein, total cholesterol, and aspartate transaminase compared to TT allele carriers with a p-value of 0.001. Additionally, 28.2% of patients showed a good response to atorvastatin, 35% had a moderate response, and 39% demonstrated poor or no response. Atherogenic Index of Plasma results indicated that 85% of patients were at high risk for ischemic heart disease and atherosclerosis, while Castelli Risk Indices I and II revealed that 54% and 21% patients, respectively, were at high risk for atherosclerosis and ischemic heart disease. Significant differences in body mass index, lipid profiles, and atherogenic Index of Plasma were observed between different age and duration of treatment groups.
Conclusion: The rs28942111 single nucleotide polymorphism in the PCSK9 gene appears to have a notable influence on lipid profiles and individual variability in response to atorvastatin therapy. Despite ongoing statin treatment, a considerable number of patients remain at elevated risk for ischemic heart disease, as reflected by atherogenic indices such as Atherogenic Index of Plasma and the Castelli Risk Indices. These findings indicate the importance of incorporating genetic screening and atherogenic risk evaluation into the management of hyperlipidemia, and using more personalized and effective therapeutic strategies.