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

Holmes, Michael V., Kartsonaki, Christiana, Boxall, Ruth, Lin, Kuang, Reeve, Nicola, Yu, Canqing, Lv, Jun, Bennett, Derrick A., Hill, Michael R., Yang, Ling, Chen, Yiping, Du, Huaidong, Turnbull, Iain, Collins, Rory, Clarke, Robert J., Tobin, Martin D., Li, Liming, Millwood, Iona Y., Chen, Zhengming, Walters, Robin G., Chen, Junshi, Chen, Zhengming, Clarke, Robert, Collins, Rory, Guo, Yu, Li, Liming, Wang, Chen, Lv, Jun, Peto, Richard, Walters, Robin, Avery, Daniel, Bennett, Derrick, Boxall, Ruth, Burgess, Sushila, Chan, Ka Hung, Chen, Yiping, Chen, Zhengming, Clarke, Johnathan, Clarke, Robert, Du, Huaidong, Edris, Ahmed, Fry, Hannah, Gilbert, Simon, Hill, Mike, Im, Pek Kei, Iona, Andri, Kakkoura, Maria, Kartsonaki, Christiana, Lam, Hubert, Lin, Kuang, Mazidi, Mohsen, Millwood, Iona, Morris, Sam, Nie, Qunhua, Pozarickij, Alfred, Ryder, Paul, Said, Saredo, Schmidt, Dan, Sherliker, Paul, Stevens, Becky, Turnbull, Iain, Walters, Robin, Wang, Baihan, Wang, Lin, Wright, Neil, Yang, Ling, Yang, Xiaoming, Yao, Pang, Han, Xiao, Hou, Can, Xia, Qingmei, Liu, Chao, Lv, Jun, Pei, Pei, Yu, Canqing, Dong, Caixia, Ge, Pengfei, Ren, Xiaolan, Li, Zhongxiao, Mao, Enke, Wang, Tao, Zhang, Hui, Zhang, Xi, Chen, Jinyan, Hu, Ximin, Wang, Xiaohuan, Guo, Zhendong, Li, Huimei, Li, Yilei, Weng, Min, Wu, Shukuan, Yan, Shichun, Zou, Mingyuan, Zhou, Xue, Guo, Ziyan, Kang, Quan, Li, Yanjie, Yu, Bo, Xu, Qinai, Chang, Liang, Fan, Lei, Feng, Shixian, Zhang, Ding, Zhou, Gang, Gao, Yulian, He, Tianyou, He, Pan, Hu, Chen, Sun, Huarong, Zhang, Xukui, Chen, Biyun, Fu, Zhongxi, Huang, Yuelong, Liu, Huilin, Xu, Qiaohua, Yin, Li, Long, Huajun, Xu, Xin, Zhang, Hao, Zhang, Libo, Chen, Naying, Liu, Duo, Tang, Zhenzhu, Chen, Ningyu, Jiang, Qilian, Lan, Jian, Li, Mingqiang, Liu, Yun, Meng, Fanwen, Meng, Jinhuai, Pan, Rong, Qin, Yulu, Wang, Ping, Wang, Sisi, Wei, Liuping, Zhou, Liyuan, Cheng, Liang, Du, Ranran, Gao, Ruqin, Li, Feifei, Li, Shanpeng, Liu, Yongmei, Ning, Feng, Pang, Zengchang, Sun, Xiaohui, Tian, Xiaocao, Wang, Shaojie, Zhai, Yaoming, Zhang, Hua, Hou, Wei, Lv, Silu, Wang, Junzheng, Chen, Xiaofang, Wu, Xianping, Zhang, Ningmei, Zhou, Weiwei, Chen, Xiaofang, Li, Jianguo, Liu, Jiaqiu, Luo, Guojin, Sun, Qiang, Zhong, Xunfu, Su, Jian, Tao, Ran, Wu, Ming, Yang, Jie, Zhou, Jinyi, Zhou, Yonglin, Hu, Yihe, Hua, Yujie, Jin, Jianrong, Liu, Fang, Liu, Jingchao, Lu, Yan, Ma, Liangcai, Tang, Aiyu, Zhang, Jun, Gong, Weiwei, Hu, Ruying, Wang, Hao, Wang, Meng, Yu, Min, Chen, Lingli, Gu, Qijun, Pan, Dongxia, Wang, Chunmei, Xie, Kaixu and Zhang, Xiaoyi 2024. PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations. European Journal of Preventive Cardiology 31 (8) , pp. 1015-1025. 10.1093/eurjpc/zwae009

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Publisher:	Oxford University Press
ISSN:	2047-4873
Funders:	GlaxoSmithKline and the Medical Research Council, UK
Date of First Compliant Deposit:	14 May 2024
Date of Acceptance:	20 December 2023
Last Modified:	10 Nov 2024 03:00
URI:	https://orca.cardiff.ac.uk/id/eprint/168896

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