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

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.