PCSK9genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations

Abstract

AbstractBackgroundLowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses ofPCSK9genetic variants in large prospective biobanks can help to identify unexpected effects of PCSK9 inhibition.MethodsThe prospective China Kadoorie Biobank genotyped >100,000 participants with follow-up for fatal and non-fatal disease events. APCSK9genetic score (PCSK9-GS) was constructed using three single nucleotide polypmorphisms at thePCSK9locus associated with directly-measured LDL-C, including a loss-of-function variant (rs151193009). Logistic regression gave estimated odds ratios (ORs) forPCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1-standard deviation (SD) lower LDL-C.ResultsPCSK9-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 ofPCSK9-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).ConclusionsLDL-C-loweringPCSK9genetic 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.