PCSK9 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 A Bennett; Michael R Hill; Ling Yang; Yiping Chen; Huaidong Du; Iain Turnbull; Rory Collins; Robert J Clarke; Martin D Tobin; Liming Li; Iona Y Millwood; Zhengming Chen; Robin G Walters; China Kadoorie Biobank Collaborative Group

doi:10.1093/eurjpc/zwae009

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations

Eur J Prev Cardiol. 2024 Jan 10:zwae009. doi: 10.1093/eurjpc/zwae009. Online ahead of print.

Authors

Michael V Holmes^{1

2}, Christiana Kartsonaki^{1

2}, Ruth Boxall^{1

2}, Kuang Lin², Nicola Reeve³, Canqing Yu^{4

5

6}, Jun Lv^{4

5

6}, Derrick A Bennett^{1

2}, Michael R Hill^{1

2}, Ling Yang^{1

2}, Yiping Chen^{1

2}, Huaidong Du^{1

2}, Iain Turnbull², Rory Collins², Robert J Clarke², Martin D Tobin^{3

7}, Liming Li^{4

5

6}, Iona Y Millwood^{1

2}, Zhengming Chen^{1

2}, Robin G Walters^{1

2}; China Kadoorie Biobank Collaborative Group

Collaborators

China Kadoorie Biobank Collaborative Group:
Junshi Chen, Zhengming Chen, Robert Clarke, Rory Collins, Yu Guo, 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 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, Liang Chang, Lei Fan, Shixian Feng, Ding Zhang, Gang Zhou, Yulian Gao, Tianyou He, Pan He, Chen Hu, Huarong Sun, Xukui Zhang, Biyun Chen, Zhongxi Fu, Yuelong Huang, Huilin Liu, Qiaohua Xu, Li Yin, Huajun Long, Xin Xu, Hao Zhang, Libo Zhang, Naying Chen, Duo Liu, Zhenzhu Tang, Ningyu Chen, Qilian Jiang, Jian Lan, Mingqiang Li, Yun Liu, Fanwen Meng, Jinhuai Meng, Rong Pan, Yulu Qin, Ping Wang, Sisi Wang, Liuping Wei, Liyuan Zhou, Liang Cheng, Ranran Du, Ruqin Gao, Feifei Li, Shanpeng Li, Yongmei Liu, Feng Ning, Zengchang Pang, Xiaohui Sun, Xiaocao Tian, Shaojie Wang, Yaoming Zhai, Hua Zhang, Wei Hou, Silu Lv, Junzheng Wang, Xiaofang Chen, Xianping Wu, Ningmei Zhang, Weiwei Zhou, Xiaofang Chen, Jianguo Li, Jiaqiu Liu, Guojin Luo, Qiang Sun, Xunfu Zhong, Jian Su, Ran Tao, Ming Wu, Jie Yang, Jinyi Zhou, Yonglin Zhou, Yihe Hu, Yujie Hua, Jianrong Jin, Fang Liu, Jingchao Liu, Yan Lu, Liangcai Ma, Aiyu Tang, Jun Zhang, Weiwei Gong, Ruying Hu, Hao Wang, Meng Wang, Min Yu, Lingli Chen, Qijun Gu, Dongxia Pan, Chunmei Wang, Kaixu Xie, Xiaoyi Zhang

Affiliations

¹ Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
² Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³ Department of Population Health Sciences, University of Leicester, Leicester, UK.
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
⁵ Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China.
⁶ Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
⁷ National Institute for Health and Care Research, Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.

PMID: 38198221
DOI: 10.1093/eurjpc/zwae009

Abstract

Aim: 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: 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-GS). Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1SD lower LDL-C.

Results: PCSK9-GS was associated 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=7.3x10-4). 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=5.4x10-5) and self-reported asthma (pooled OR 1.17 ([1.04-1.30]; P=0.0071). There was no association of a polygenic LDL-C score with COPD hospitalisation, COPD exacerbation, or URTI.

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. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.

Keywords: Mendelian randomisation; PCSK9 inhibition; chronic obstructive pulmonary disease; exacerbation; target-mediated adverse effects; upper respiratory tract infection.

Plain language 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 hospitalisation with chronic obstructive respiratory 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 hospitalised and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

Abstract

Plain language summary

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