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Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults

Nature Medicine volume 25, pages 569–574 (2019)Cite this article

Subjects

Abstract

Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China1,2. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS1,2. Stroke incidence and ICH proportion are higher in China than in Western populations3,4,5, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD)6,7, but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD8,9,10. Mendelian randomization studies of LDL-C and IS have reported conflicting results11,12,13, and concerns about the excess risks of ICH associated with lowering LDL-C14,15 may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.

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Fig. 1: Adjusted RRs for risk of IS and ICH by fifths of usual concentrations of LDL-C, HDL-C, and triglycerides in observational analyses in the CKB.
Fig. 2: Adjusted RRs for risk of IS and ICH associated with 1 mmol l−1 lower LDL-C in observational and genetic analyses in the CKB, and in randomized trials of LDL-C-lowering drug treatment in Western populations.
Fig. 3: Predicted number of events avoided for IS, MCEs, and ICH per 10,000 patients treated by lowering LDL-C by 1 mmol l−1 with statins for 5 years in Chinese adults with different levels of vascular risk.

Data availability

R.Clarke, D.B., L.L., and Z.C. have full access to all the study data and take responsibility for the integrity of the data and the accuracy of the data analysis. Data from the baseline survey, first resurvey, and cause-specific mortality are available to all bona fide researchers (www.ckbiobank.org). Additional data can also be made available on a collaborative basis by contacting the study investigators. All data requests are reviewed monthly by the CKB Data Access Committee, which is composed of senior scientists from Beijing and Oxford.

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Acknowledgements

We wish to thank the participants, project staff, and staff of the China Center for Disease Control and its regional offices for access to death and disease registries. The Chinese National Health Insurance scheme provided electronic linkage to all hospitalization data. The CKB study is jointly coordinated by the University of Oxford and the Chinese Academy of Medical Sciences. The funding body for the baseline survey was the Kadoorie Charitable Foundation, Hong Kong, China. Z.C. was funded for the long-term continuation of the study by Wellcome Trust grants (nos. 202922/Z/16/Z, 104085/Z/14/Z, and 088158/Z/09/Z). L.L. was funded by the National Natural Science Foundation of China (grant nos. 81390540, 81390541, and 81390544) and the National Key Research and Development Program of China (grant nos. 2016YFC0900500, 2016YFC0900501, 2016YFC0900504, and 2016YFC1303904). Core funding was also provided to the Clinical Trial Service Unit, University of Oxford, by the British Heart Foundation, the UK Medical Research Council, and Cancer Research UK. L.S. received a Clarendon Scholarship from the University of Oxford. The funders played no role in the design or conduct of the study, including data collection, management, analysis, or interpretation of the results; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Luanluan Sun, Robert Clarke, Derrick Bennett, Rory Collins, Richard Peto, Zhengming Chen, Zhengming Chen, Robert Clarke, Rory Collins, Richard Peto, Robin Walters, Daniel Avery, Derrick Bennett, Ruth Boxall, Fiona Bragg, Yumei Chang, Yiping Chen, Zhengming Chen, Robert Clarke, Huaidong Du, Simon Gilbert, Alex Hacker, Michael Holmes, Christiana Kartsonaki, Rene Kerosi, Garry Lancaster, Kuang Lin, John McDonnell, Iona Millwood, Qunhua Nie, Jayakrishnan Radhakrishnan, Paul Ryder, Sam Sansome, Dan Schmidt, Rajani Sohoni, Iain Turnbull, Robin Walters, Jenny Wang, Lin Wang, Neil Wright, Ling Yang & Xiaoming Yang

  2. Chinese Academy of Medical Sciences, Beijing, China

    Yu Guo, Zheng Bian, Yu Guo, Zheng Bian, Yu Guo, Xiao Han, Can Hou, Biao Jing, Chao Liu, Pei Pei & Yunlong Tan

  3. MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Robin G. Walters, Michael Hill, Sarah Parish, Iona Y. Millwood & Yiping Chen

  4. Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China

    Canqing Yu, Jun Lv, Liming Li, Liming Li, Jun Lv, Jun Lv & Canqing Yu

  5. China National Center For Food Safety Risk Assessment, Beijing, China

    Junshi Chen & Junshi Chen

  6. NCD Prevention and Control Department, Qingdao CDC, Qingdao, China

    Zengchang Pang, Ruqin Gao, Shanpeng Li, Shaojie Wang, Yongmei Liu, Ranran Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang, Yaoming Zhai, Feng Ning, Xiaohui Sun & Feifei Li

  7. NCD Prevention and Control Department, Licang CDC, Qingdao, China

    Silu Lv, Junzheng Wang & Wei Hou

  8. NCD Prevention and Control Department, Heilongjiang CDC, Harbin, China

    Mingyuan Zeng, Ge Jiang & Xue Zhou

  9. NCD Prevention and Control Department, Nangang CDC, Harbin, China

    Liqiu Yang, Hui He, Bo Yu, Yanjie Li, Qinai Xu, Quan Kang & Ziyan Guo

  10. NCD Prevention and Control Department, Hainan Provincial CDC, Haikou, China

    Dan Wang, Ximin Hu, Hongmei Wang, Jinyan Chen, Yan Fu, Zhenwang Fu & Xiaohuan Wang

  11. NCD Prevention and Control Department, Meilan CDC, Meilan, Haikou, China

    Min Weng, Zhendong Guo, Shukuan Wu, Yilei Li, Huimei Li & Zhifang Fu

  12. NCD Prevention and Control Department, Jiangsu Provincial CDC, Nanjing, China

    Ming Wu, Yonglin Zhou, Jinyi Zhou, Ran Tao, Jie Yang & Jian Su

  13. NCD Prevention and Control Department, Wuzhong CDC, Wuzhong, Suzhou, China

    Fang Liu, Jun Zhang, Yihe Hu, Yan Lu, Liangcai Ma, Aiyu Tang, Shuo Zhang, Jianrong Jin & Jingchao Liu

  14. NCD Prevention and Control Department, Guangxi Provincial CDC, Nanning, China

    Zhenzhu Tang, Naying Chen & Ying Huang

  15. NCD Prevention and Control Department, Liuzhou CDC, Liubei, Liuzhou, China

    Mingqiang Li, Jinhuai Meng, Rong Pan, Qilian Jiang, Jian Lan, Yun Liu, Liuping Wei, Liyuan Zhou, Ningyu Chen, Ping Wang, Fanwen Meng, Yulu Qin & Sisi Wang

  16. NCD Prevention and Control Department, Sichuan Provincial CDC, Chengdu, China

    Xianping Wu, Ningmei Zhang, Xiaofang Chen & Weiwei Zhou

  17. NCD Prevention and Control Department, Pengzhou CDC, Pengzhou, Chengdu, China

    Guojin Luo, Jianguo Li, Xiaofang Chen, Xunfu Zhong, Jiaqiu Liu & Qiang Sun

  18. NCD Prevention and Control Department, Gansu Provincial CDC, Lanzhou, China

    Pengfei Ge, Xiaolan Ren & Caixia Dong

  19. NCD Prevention and Control Department, Maijixiang CDC, Maijixiang, Tianshui, China

    Hui Zhang, Enke Mao, Xiaoping Wang, Tao Wang & Xi Zhang

  20. NCD Prevention and Control Department, Henan Provincial CDC, Zhengzhou, China

    Ding Zhang, Gang Zhou, Shixian Feng, Liang Chang & Lei Fan

  21. NCD Prevention and Control Department, Huixian CDC, Huixian, China

    Yulian Gao, Tianyou He, Huarong Sun, Pan He, Chen Hu, Xukui Zhang & Huifang Wu

  22. NCD Prevention and Control Department, Zhejiang Provincial CDC, Hangzhou, China

    Min Yu, Ruying Hu & Hao Wang

  23. NCD Prevention and Control Department, Tongxiang CDC, Tongxiang, China

    Yijian Qian, Chunmei Wang, Kaixu Xie, Lingli Chen, Yidan Zhang, Dongxia Pan & Qijun Gu

  24. NCD Prevention and Control Department, Hunan Provincial CDC, Changsha, China

    Yuelong Huang, Biyun Chen, Li Yin, Huilin Liu, Zhongxi Fu & Qiaohua Xu

  25. NCD Prevention and Control Department, Liuyang CDC, Liuyang, China

    Xin Xu, Hao Zhang, Huajun Long, Xianzhi Li, Libo Zhang & Zhe Qiu

Authors
  1. Luanluan Sun
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  2. Robert Clarke
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  3. Derrick Bennett
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  4. Yu Guo
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  5. Robin G. Walters
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  6. Michael Hill
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  7. Sarah Parish
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  8. Iona Y. Millwood
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  9. Zheng Bian
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  10. Yiping Chen
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  11. Canqing Yu
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  12. Jun Lv
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  13. Rory Collins
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  14. Junshi Chen
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  15. Richard Peto
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  16. Liming Li
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  17. Zhengming Chen
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Consortia

on behalf of the China Kadoorie Biobank Collaborative Group

International Steering Committee

  • Junshi Chen
  • , Zhengming Chen
  • , Robert Clarke
  • , Rory Collins
  • , Yu Guo
  • , Liming Li
  • , Jun Lv
  • , Richard Peto
  •  & Robin Walters

International Co-ordinating Centre, Oxford

  • Daniel Avery
  • , Derrick Bennett
  • , Ruth Boxall
  • , Fiona Bragg
  • , Yumei Chang
  • , Yiping Chen
  • , Zhengming Chen
  • , Robert Clarke
  • , Huaidong Du
  • , Simon Gilbert
  • , Alex Hacker
  • , Michael Holmes
  • , Christiana Kartsonaki
  • , Rene Kerosi
  • , Garry Lancaster
  • , Kuang Lin
  • , John McDonnell
  • , Iona Millwood
  • , Qunhua Nie
  • , Jayakrishnan Radhakrishnan
  • , Paul Ryder
  • , Sam Sansome
  • , Dan Schmidt
  • , Rajani Sohoni
  • , Iain Turnbull
  • , Robin Walters
  • , Jenny Wang
  • , Lin Wang
  • , Neil Wright
  • , Ling Yang
  •  & Xiaoming Yang

National Co-ordinating Centre, Beijing

  • Zheng Bian
  • , Yu Guo
  • , Xiao Han
  • , Can Hou
  • , Biao Jing
  • , Chao Liu
  • , Jun Lv
  • , Pei Pei
  • , Yunlong Tan
  •  & Canqing Yu

Regional Co-ordinating Centres

  • Zengchang Pang
  • , Ruqin Gao
  • , Shanpeng Li
  • , Shaojie Wang
  • , Yongmei Liu
  • , Ranran Du
  • , Yajing Zang
  • , Liang Cheng
  • , Xiaocao Tian
  • , Hua Zhang
  • , Yaoming Zhai
  • , Feng Ning
  • , Xiaohui Sun
  • , Feifei Li
  • , Silu Lv
  • , Junzheng Wang
  • , Wei Hou
  • , Mingyuan Zeng
  • , Ge Jiang
  • , Xue Zhou
  • , Liqiu Yang
  • , Hui He
  • , Bo Yu
  • , Yanjie Li
  • , Qinai Xu
  • , Quan Kang
  • , Ziyan Guo
  • , Dan Wang
  • , Ximin Hu
  • , Hongmei Wang
  • , Jinyan Chen
  • , Yan Fu
  • , Zhenwang Fu
  • , Xiaohuan Wang
  • , Min Weng
  • , Zhendong Guo
  • , Shukuan Wu
  • , Yilei Li
  • , Huimei Li
  • , Zhifang Fu
  • , Ming Wu
  • , Yonglin Zhou
  • , Jinyi Zhou
  • , Ran Tao
  • , Jie Yang
  • , Jian Su
  • , Fang Liu
  • , Jun Zhang
  • , Yihe Hu
  • , Yan Lu
  • , Liangcai Ma
  • , Aiyu Tang
  • , Shuo Zhang
  • , Jianrong Jin
  • , Jingchao Liu
  • , Zhenzhu Tang
  • , Naying Chen
  • , Ying Huang
  • , Mingqiang Li
  • , Jinhuai Meng
  • , Rong Pan
  • , Qilian Jiang
  • , Jian Lan
  • , Yun Liu
  • , Liuping Wei
  • , Liyuan Zhou
  • , Ningyu Chen
  • , Ping Wang
  • , Fanwen Meng
  • , Yulu Qin
  • , Sisi Wang
  • , Xianping Wu
  • , Ningmei Zhang
  • , Xiaofang Chen
  • , Weiwei Zhou
  • , Guojin Luo
  • , Jianguo Li
  • , Xiaofang Chen
  • , Xunfu Zhong
  • , Jiaqiu Liu
  • , Qiang Sun
  • , Pengfei Ge
  • , Xiaolan Ren
  • , Caixia Dong
  • , Hui Zhang
  • , Enke Mao
  • , Xiaoping Wang
  • , Tao Wang
  • , Xi Zhang
  • , Ding Zhang
  • , Gang Zhou
  • , Shixian Feng
  • , Liang Chang
  • , Lei Fan
  • , Yulian Gao
  • , Tianyou He
  • , Huarong Sun
  • , Pan He
  • , Chen Hu
  • , Xukui Zhang
  • , Huifang Wu
  • , Min Yu
  • , Ruying Hu
  • , Hao Wang
  • , Yijian Qian
  • , Chunmei Wang
  • , Kaixu Xie
  • , Lingli Chen
  • , Yidan Zhang
  • , Dongxia Pan
  • , Qijun Gu
  • , Yuelong Huang
  • , Biyun Chen
  • , Li Yin
  • , Huilin Liu
  • , Zhongxi Fu
  • , Qiaohua Xu
  • , Xin Xu
  • , Hao Zhang
  • , Huajun Long
  • , Xianzhi Li
  • , Libo Zhang
  •  & Zhe Qiu

Contributions

L.S., R.Clarke, D.B., R.P., and Z.C. designed and planned the analysis and manuscript. L.S. performed the data analyses and wrote the first draft of the manuscript. R.Clarke, D.B., S.P., R.P., and Z.C. provided scientific interpretation of the results and revised the manuscript. R.Clarke, Z.C., L.L., R.P., R.Collins, R.W., J.L., and J.C., as members of the CKB steering committee, designed and supervised the overall conduct of the study and obtained the funding. Y.G., Y.C., Z.B., C.Y., and Z.C. coordinated the data acquisition (for baseline, resurveys, and long-term follow-up). R.W., Y.G., I.M., Z.B., and M.H. coordinated the genotyping analyses in China and the laboratory analyses in Oxford. All authors provided critical comments on the final version of the manuscript.

Corresponding authors

Correspondence to Robert Clarke or Zhengming Chen.

Ethics declarations

Competing interests

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Extended data

Extended Data Fig. 1 Effect of progressive adjustment for potential confounders on the risk of IS and ICH with usual LDL-C.

Cox regression was used to estimate adjusted RRs (95% confidence intervals (CI)) for the risk of different stroke types per 1 mmol l−1 higher concentrations of usual LDL-C. Each square has an area inversely proportional to the variance of the log risk. The horizontal lines represent the 95% CIs.

Extended Data Fig. 2 Associations of usual LDL-C with risk of IS and ICH in population subgroups at baseline.

Cox regression was used to estimate the adjusted RRs (95% CIs) for the risk of different stroke types per 1 mmol l−1 higher concentrations of usual LDL-C. Chi-squared tests were used to assess heterogeneity and trend; the d.f. are provided as subscripts. All two-sided P values were uncorrected for multiple testing. Symbols and conventions as in Extended Data Fig. 1.

Extended Data Fig. 3 Adjusted RRs for the risk of IS by usual concentrations of LDL-C and HDL-C in observational analyses in the CKB.

Symbols and conventions as in Extended Data Fig. 1. The number of IS cases and controls were 5,475 and 6,290, respectively.

Extended Data Fig. 4 Adjusted RRs for the risk of IS and ICH by usual concentrations of apolipoprotein B and A1, and lipoprotein(a) in observational analyses in the CKB.

a–c, Cox regression was used to estimate the RRs (95% CIs) for IS (N = 5,475) and ICH (N = 4,776) by fifths of usual apolipoprotein B (a), usual apolipoprotein A1 (b), and usual lipoprotein(a) (c), respectively. The line represents the slope from a weighted linear regression with the weights based on the inverse variance of the log RR. Symbols and conventions as in Extended Data Fig. 1.

Extended Data Fig. 5 Associations of the GRS for LDL-C with major vascular risk factors.

The analyses were conducted in 17,567 CKB participants with available data, adjusted for sex, age, age2, and case status. General linear regression was used to estimate s.d. differences in all traits (after rank inverse normal transformation) per 1 s.d. higher GRS. All two-sided P values were uncorrected for multiple testing.

Extended Data Fig. 6 Meta-analysis of randomized trials of LDL-C-lowering treatment with statins, ezetimibe, or PCSK9 inhibitor and risk of IS and ICH.

Study-specific RRs (95% CI) were obtained from the published results of the LDL-C-lowering trials. The overall RRs (95% CIs) were obtained by inverse variance-weighted meta-analysis of the study-specific RRs per 1 mmol l−1 lower LDL-C concentration.

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Sun, L., Clarke, R., Bennett, D. et al. Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults. Nat Med 25, 569–574 (2019). https://doi.org/10.1038/s41591-019-0366-x

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