PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations
Authors: 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 ,   China Kadoorie Biobank Collaborative Group, 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 , Zhang Xiaoyi 
Published: January 2024

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.