Aizezi Aibibanmu, Meng Fanhua, Li Xiaolei, Li Yanpeng, Abuzhalihan Jialin, Liu Fen, Gai Mintao, Adi Dilare, Ma Yi-Tong
Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, P.R. China.
J Clin Hypertens (Greenwich). 2025 Aug;27(8):e70120. doi: 10.1111/jch.70120.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) polymorphisms exhibit ethnic-specific associations with cardiovascular risk. However, their prognostic value for major adverse cardiovascular and cerebrovascular events (MACCE) in Asian populations remains undefined. This prospective cohort study enrolled 1969 patients (mean age 54.5 ± 10.7 years, 60.2% male) with hyperlipidemia and followed them for a median of 62 months (IQR 24-89 months). We evaluated the association of three PCSK9 polymorphisms (rs2483205, rs2495477, and rs562556) with metabolic parameters and MACCE. A genotype-integrated nomogram was developed using Least Absolute Shrinkage and Selection Operator (LASSO) - selected predictors and validated in an independent cohort. The rs2483205 TT, rs2495477 GG, and rs562556 GG genotypes were significantly associated with atherogenic dyslipidemia (elevated triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) [Lp(a)], all p < 0.001) and predicted MACCE risk independently of conventional factors (HR = 2.94, 95% CI: 1.80-4.80 for rs2483205 TT). The nomogram demonstrated excellent discrimination (3 and 4 year area under the curve (AUC) = 0.989, concordance index (C-index) = 0.868) and calibration (slope = 1.02, 95% CI: 0.98-1.06), with decision curve analysis confirming clinical utility across risk thresholds (20%-75%). Net Reclassification Improvement (NRI) increase of 0.059 and an Integrated Discrimination Improvement (IDI) increase of 0.022. PCSK9 genotyping provides independent prognostic value for MACCE risk stratification in hyperlipidemia, with genotype-specific effects on cardiovascular outcomes. The developed nomogram offers a precision medicine tool for individualized risk prediction and therapeutic decision-making.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）基因多态性与心血管风险存在种族特异性关联。然而，其对亚洲人群主要心血管和脑血管不良事件（MACCE）的预后价值仍不明确。这项前瞻性队列研究纳入了1969例高脂血症患者（平均年龄54.5±10.7岁，男性占60.2%），对他们进行了为期62个月的中位数随访（四分位间距为24 - 89个月）。我们评估了三种PCSK9基因多态性（rs2483205、rs2495477和rs562556）与代谢参数及MACCE的关联。使用最小绝对收缩和选择算子（LASSO）选择的预测因子构建了基因型整合列线图，并在一个独立队列中进行了验证。rs2483205 TT、rs2495477 GG和rs562556 GG基因型与致动脉粥样硬化性血脂异常（甘油三酯（TG）升高、低密度脂蛋白胆固醇（LDL-C）升高和脂蛋白(a) [Lp(a)]升高，所有p<0.001）显著相关，且独立于传统因素预测MACCE风险（rs2483205 TT的HR = 2.94，95%CI：1.80 - 4.80）。该列线图显示出出色的辨别能力（3年和4年曲线下面积（AUC） = 0.989，一致性指数（C-index） = 0.868）和校准度（斜率 = 1.02，95%CI：0.98 - 1.06），决策曲线分析证实了其在各风险阈值（20% - 75%）下的临床实用性。净重新分类改善（NRI）增加了0.059，综合辨别改善（IDI）增加了0.022。PCSK9基因分型为高脂血症患者的MACCE风险分层提供了独立的预后价值，对心血管结局有基因型特异性影响。所构建的列线图为个性化风险预测和治疗决策提供了精准医学工具。
