Identification of protein targets for dyslipidaemia and cardiovascular diseases among people with South Asian ancestry: a mendelian randomisation study

IF 6.2 Q1 HEALTH CARE SCIENCES & SERVICES

The Lancet regional health. Southeast Asia Pub Date : 2025-07-04 DOI:10.1016/j.lansea.2025.100621

Siwei Wu , Devendra Meena , Alexander Smith , Jingxian Huang , Georg W. Otto , Yi-Hsuan Ko , James Yarmolinsky , Dipender Gill , Anand Rohatgi , Abbas Dehghan , Ioanna Tzoulaki

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Abstract

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 NIH R01 HL162300-02.

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南亚血统人群血脂异常和心血管疾病的蛋白靶点鉴定：一项孟德尔随机研究

背景：南亚人被认为有较高的血脂异常风险，这是心血管疾病（cvd）的一个可改变的危险因素。我们的目的是确定南亚血统人群中血脂异常和心血管疾病的蛋白质靶点。方法采用双样本孟德尔随机化（MR）方法，并结合MR- egger、加权中位数、共定位和广义MR (GMR)，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，我们比较了血浆蛋白对南亚和欧洲人群血脂的影响。研究结果：我们鉴定了29种可能导致至少一种脂质测量的遗传代理蛋白，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)，蛋白转化酶枯草杆菌素/kexin 9型（PCSK9）和钙粘蛋白EGF LAG七通g型受体2 （CELSR2）。值得注意的是，与南亚人相比，欧洲人的PCSK9与LDL-C的相关性更强(β欧洲人= 0.37；95% CI 0.36, 0.38， β南亚= 0.16；95% ci 0.11, 0.21)。观察性分析表明，南亚人的PCSK9水平与LDL-C水平之间存在统计学意义上的相互作用，与其他种族相比，南亚人的作用明显较低(PCSK9 * South Asian；β =−0.14；95% ci -0.174, - 0.107)。此外，我们发现CELSR2也与南亚人的冠状动脉疾病有关。我们的研究强调了南亚血浆蛋白、血脂异常和心血管疾病之间的潜在因果关系，并强调了蛋白靶点，包括CELSR2、PCSK9、ANGPTL3和载脂蛋白(a) （LPA）。值得注意的是，我们的研究表明PCSK9对南亚人LDL-C的影响明显弱于欧洲人。本研究由英国心脏基金会卓越研究奖(4)（RE/24/130023）资助。IT和AR由NIH R01 HL162300-02支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

The Lancet regional health. Southeast Asia

CiteScore

2.20

自引率

0.00%

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