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• W4385952826 abstract "Abstract Background Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large prospective biobanks can help to identify unexpected effects of PCSK9 inhibition. Methods The prospective China Kadoorie Biobank genotyped >100,000 participants with follow-up for fatal and non-fatal disease events. A PCSK9 genetic score ( PCSK9 -GS) was constructed using three single nucleotide polypmorphisms at the PCSK9 locus associated with directly-measured LDL-C, including a loss-of-function variant (rs151193009). Logistic regression gave estimated odds ratios (ORs) for PCSK9 -GS associations with CVD and non-CVD outcomes, scaled to 1-standard deviation (SD) lower LDL-C. Results PCSK9 -GS was associated with lower apolipoprotein B, and with lower risks of carotid plaque (n=8340 cases; OR=0.61 [95%CI: 0.45-0.83]; P=0.0015), major occlusive vascular events (n=15,752; 0.80 [0.67-0.95]; P=0.011), and ischaemic stroke (n=11,467; 0.80 [0.66-0.98]; P=0.029). However, PCSK9 -GS was also associated with higher risk of hospitalisation with chronic obstructive pulmonary disease (COPD: n=6836; 1.38 [1.08-1.76]; P=0.0089), and with even higher risk of fatal exacerbations among individuals with pre-existing COPD (n=730; 3.61 [1.71-7.60]; P=7.3×10 −4 ). Risk of acute upper respiratory tract infection (URTI) was also increased (n=1,095; 2.18 [1.34-3.53]; P=0.0016), as previously reported in UK Biobank, with a pooled OR after meta-analysis of 1.87 ([1.38-2.54]; P=5.4×10 −5 ). We also replicated a previously-reported association with self-reported asthma (pooled OR 1.17 ([1.04-1.30]; P=0.0071). There was heterogeneity between the associations of PCSK9 -GS and a polygenic LDL-C score for each of COPD hospitalisation (P-het=0.015), fatal COPD exacerbation (P-het=0.0012), and URTI (P-het=0.013). Conclusions LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease, but higher risks of respiratory diseases which appear unrelated to LDL-C. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections." @default.
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• W4385952826 date "2023-08-16" @default.
• W4385952826 modified "2023-10-05" @default.
• W4385952826 title "<i>PCSK9</i>genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations" @default.
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• W4385952826 doi "https://doi.org/10.1101/2023.08.15.23294117" @default.
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