Khaleqsefat Esmat, Rasul Khder Hussein, Kheder Ramiar Kamal, Baban Sonia, Baban Jamil
Department of Nutrition and Dietetics, Cihan University-Erbil, Erbil, , Kurdistan Region, Iraq.
Department of Biology, College of science, Salahaddin University-Erbil, Erbil, , Kurdistan Region, Iraq.
Sci Rep. 2025 Jan 2;15(1):288. doi: 10.1038/s41598-024-75461-7.
Dyslipidemia, an imbalance in blood lipid levels, is a frequent complication of type 2 diabetes mellitus (DM2) and heightens the risk of cardiovascular diseases (CVDs). Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, are potent competitive inhibitors that reduce plasma cholesterol levels. However, individual responses to statins can vary markedly, possibly due to genetic variations in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. This study aimed to investigate the pharmacogenetic relationship between the HMGCR gene and hypercholesterolemia in type 2 diabetes mellitus patients who respond differently to atorvastatin, as well as in healthy individuals. Ninety participants were involved, including sixty with type 2 diabetes mellitus and hypercholesterolemia, and thirty healthy individuals. They were randomly assigned to three groups: responsive (received atorvastatin 40 mg), non-responsive (also received atorvastatin 40 mg), and control. Both responsive and non-responsive groups underwent fasting. Biochemical tests were conducted, followed by genetic analysis to identify mutations in the HMGCR gene. The effects of statins in each group were assessed using analysis of variance (ANOVA) and post hoc Tukey's Honestly Significant Difference (HSD) analysis. Atorvastatin 40 mg was administered to assess its efficacy in reducing cholesterol levels in patients with hypercholesterolemia and type 2 diabetes mellitus. The control group exhibited similar cholesterol levels to the responsive group (cholesterol < 200 mg/dl). However, both control and responsive groups significantly differed from the non-responsive group, which had markedly elevated cholesterol levels (> 240 mg/dl). Genetic analysis revealed a cytosine nucleotide insertion in the catalytic domain of the HMGCR gene in only two non-responsive participants to atorvastatin 40 mg therapy. These two patients showed non-responsiveness to atorvastatin 40 mg due to a genetic mutation in the HMGCR gene. This mutation altered the amino acid sequence in the flap domain, replacing isoleucine with a stop codon. As a result, translation was prematurely terminated, leading to the production of truncated proteins.
血脂异常，即血液脂质水平失衡，是2型糖尿病（DM2）的常见并发症，会增加心血管疾病（CVD）的风险。他汀类药物可抑制3-羟基-3-甲基戊二酰辅酶A还原酶，是强效竞争性抑制剂，可降低血浆胆固醇水平。然而，个体对他汀类药物的反应可能有显著差异，这可能是由于3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）基因的遗传变异所致。本研究旨在探讨HMGCR基因与2型糖尿病患者高胆固醇血症之间的药物遗传学关系，这些患者对阿托伐他汀的反应各不相同，同时也研究该基因与健康个体的关系。研究共纳入90名参与者，其中60名患有2型糖尿病和高胆固醇血症，30名健康个体。他们被随机分为三组：反应组（服用40毫克阿托伐他汀）、无反应组（也服用40毫克阿托伐他汀）和对照组。反应组和无反应组均进行禁食。进行生化检测，随后进行基因分析以确定HMGCR基因中的突变。使用方差分析（ANOVA）和事后Tukey's Honestly Significant Difference（HSD）分析评估每组中他汀类药物的效果。给予40毫克阿托伐他汀以评估其降低高胆固醇血症和2型糖尿病患者胆固醇水平的疗效。对照组的胆固醇水平与反应组相似（胆固醇<200毫克/分升）。然而，对照组和反应组与无反应组均有显著差异，无反应组的胆固醇水平明显升高（>240毫克/分升）。基因分析显示，在仅两名对40毫克阿托伐他汀治疗无反应的参与者中，HMGCR基因的催化结构域存在胞嘧啶核苷酸插入。这两名患者由于HMGCR基因的基因突变而对40毫克阿托伐他汀无反应。该突变改变了瓣状结构域中的氨基酸序列，用终止密码子取代了异亮氨酸。结果，翻译提前终止，导致产生截短的蛋白质。
