<i>PCSK9</i> genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations
Michael V. Holmes, Christiana Kartsonaki, Ruth Boxall, Kuang Lin, Nicola Reeve, Canqing Yu, Jun Lv, Derrick Bennett, Michael Hill, Ling Yang, Yiping Chen, Huaidong Du, Iain Turnbull, Rory Collins, Robert Clarke, Martin D. Tobin, Liming Li, Iona Y. Millwood, Zhengming Chen, Robin Walters, China Kadoorie Biobank Collaborative Group, Junshi Chen, Zhengming Chen, Robert Clarke, Rory Collins, Guo Yu, Liming Li, Chen Wang, Jun Lv, Richard Peto, Robin Walters, Daniel Avery, Derrick Bennett, Ruth Boxall, Sushila Burgess, Ka Hung Chan, Yiping Chen, Zhengming Chen, Johnathan Clarke, Robert Clarke, Huaidong Du, Ahmed Edris, Hannah Fry, Simon Gilbert, Mike Hill, Pek Kei Im, Andri Iona, Maria Kakkoura, Christiana Kartsonaki, Hubert Lam, Kuang Lin, Mohsen Mazidi, Iona Y. Millwood, Sam Morris, Qunhua Nie, Alfred Pozarickij, Paul Ryder, Saredo Said, Dan Schmidt, Paul Sherliker, Becky Stevens, Iain Turnbull, Robin Walters, Baihan Wang, Lin Wang, Neil Wright, Ling Yang, Xiaoming Yang, Pang Yao, Xiao Han, Can Hou, Qingmei Xia, Chao Liu, Jun Lv, Pei Pei, Canqing Yu, Caixia Dong, Pengfei Ge, Xiaolan Ren, Zhongxiao Li, Enke Mao, Tao Wang, Hui Zhang, Xi Zhang, Jinyan Chen, Ximin Hu, Xiaohuan Wang, Zhendong Guo, Huimei Li, Yilei Li, Min Weng, Shukuan Wu, Shichun Yan, Mingyuan Zou, Xue Zhou, Ziyan Guo, Quan Kang, Yanjie Li, Bo Yu, Qinai Xu
Abstract
AIMS: 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 biobanks can help to identify unexpected effects of PCSK9 inhibition. METHODS AND RESULTS: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 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 hospitalization 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 amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI. CONCLUSION: The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections. LAY SUMMARY: Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.