南亚裔人群中血脂异常和心血管疾病蛋白质靶点的鉴定：一项孟德尔随机化研究
Identification of protein targets for dyslipidaemia and cardiovascular diseases among people with South Asian ancestry: a mendelian randomisation study.
作者信息
Wu Siwei, Meena Devendra, Smith Alexander, Huang Jingxian, Otto Georg W, Ko Yi-Hsuan, Yarmolinsky James, Gill Dipender, Rohatgi Anand, Dehghan Abbas, Tzoulaki Ioanna
机构信息
Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, China.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
出版信息
Lancet Reg Health Southeast Asia. 2025 Jul 4;39:100621. doi: 10.1016/j.lansea.2025.100621. eCollection 2025 Aug.
BACKGROUND
South Asians are considered to be at higher risk of dyslipidaemia, a modifiable risk factor for cardiovascular diseases (CVDs). We aimed to identify protein targets for dyslipidaemia and CVDs among people with South Asian ancestry.
METHODS
We used a two-sample mendelian randomisation (MR) approach, supplemented with MR-Egger, weighted median, colocalisation, and generalised MR (GMR), to evaluate the effect of 2800 plasma proteins on high/low/non-high-density lipoprotein cholesterol (HDL-C/LDL-C/non-HDL-C), total cholesterol, and triglycerides. Observational analyses were conducted on MR findings with strong colocalisation (posterior probability ≥ 80%) and GMR evidence. Univariate MR assessed lipid-associated proteins' effect on CVDs. Finally, we compared the effects of plasma proteins on lipids between South Asian and European populations.
FINDINGS
We identified 29 genetically proxied proteins potentially causal to at least one lipid measure, 12 of which showed strong colocalisation and GMR evidence, including angiopoietin-related protein 3 (ANGPTL3), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2). Notably, PCSK9 demonstrated a stronger association with LDL-C in Europeans compared to South Asians (βEuropean = 0.37; 95% CI 0.36, 0.38, βSouth Asian = 0.16; 95% CI 0.11, 0.21). Observational analysis suggested statistically significant interaction between PCSK9 levels with LDL-C levels in South Asians with South Asians having a significantly lower effect compared to other ethnicities (PCSK9∗South Asian; β = -0.14; 95% CI -0.174, -0.107). Additionally, we showed that CELSR2 is also linked with coronary artery disease in South Asians.
INTERPRETATION
Our study highlighted potential causal links between plasma proteins, dyslipidaemia, and CVDs in South Asians and highlighted protein targets, including CELSR2, PCSK9, ANGPTL3, and Apolipoprotein(a) (LPA). Notably, our study indicated that PCSK9 has a significantly weaker effect on LDL-C in South Asians than Europeans.
FUNDING
This work is supported by the British Heart Foundation Research Excellence Award (4) (RE/24/130023). IT and AR are supported by NIHR01 HL162300-02.
背景
南亚人被认为患血脂异常的风险更高，血脂异常是心血管疾病（CVD）的一个可改变的风险因素。我们旨在确定南亚裔人群中血脂异常和心血管疾病的蛋白质靶点。
方法
我们采用两样本孟德尔随机化（MR）方法，并辅以MR-Egger、加权中位数、共定位和广义MR（GMR），以评估2800种血浆蛋白对高/低/非高密度脂蛋白胆固醇（HDL-C/LDL-C/非HDL-C）、总胆固醇和甘油三酯的影响。对具有强共定位（后验概率≥80%）和GMR证据的MR结果进行观察性分析。单变量MR评估脂质相关蛋白对心血管疾病的影响。最后，我们比较了南亚和欧洲人群中血浆蛋白对血脂的影响。
结果
我们确定了29种基因代理蛋白可能对至少一种血脂指标有因果关系，其中12种显示出强共定位和GMR证据，包括血管生成素相关蛋白3（ANGPTL3）、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）和钙黏蛋白EGF LAG七次跨膜G型受体2（CELSR2）。值得注意的是，与南亚人相比，PCSK9在欧洲人与低密度脂蛋白胆固醇的关联更强（β欧洲人=0.37；95%CI 0.36，0.38，β南亚人=0.16；95%CI 0.11，0.21）。观察性分析表明，在南亚人中，PCSK9水平与低密度脂蛋白胆固醇水平之间存在统计学上显著的相互作用，与其他种族相比，南亚人的影响显著较低（PCSK9∗南亚人；β=-0.14；95%CI -0.174，-0.107）。此外，我们表明CELSR2也与南亚人的冠状动脉疾病有关。
解读
我们的研究强调了南亚人中血浆蛋白、血脂异常和心血管疾病之间潜在的因果联系，并突出了包括CELSR2、PCSK9、ANGPTL3和载脂蛋白（a）（LPA）在内的蛋白质靶点。值得注意的是，我们的研究表明，PCSK9对南亚人低密度脂蛋白胆固醇的影响明显弱于欧洲人。
资助
这项工作得到了英国心脏基金会卓越研究奖（4）（RE/24/130023）的支持。IT和AR得到了NIHR01 HL162300-02的支持。
Zotero 插件