Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study
Abstract
BACKGROUND: Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain. METHODS: We measured plasma levels of Lp(a) in a nested case–control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia. RESULTS: In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of myocardial infarction and IS, but not with intracerebral hemorrhage. In genome-wide association analysis, we identified 29 single nucleotide polymorphisms independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese individuals. In UK Biobank, the lead Chinese variants identified in CKB were replicated in 1260 Chinese individuals, but explained only 10% of variance in Lp(a) in European individuals. In Mendelian randomization analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all cardiovascular disease outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically predicted Lp(a) levels for myocardial infarction were 3-fold greater than for total IS (rate ratio, 0.78 [95% CI, 0.76–0.81] versus 0.94 [0.92–0.96]), but were similar to those for large-artery IS (0.80 [0.73–0.87]; n=8134). There were weaker associations with cardioembolic IS (0.92 [95% CI, 0.86–0.98]; n=11 730), and no association with small-vessel IS (0.99 [0.91–1.07]; n=12 343) or with intracerebral hemorrhage (1.08 [0.96–1.21]; n=5845). CONCLUSIONS: The effects of Lp(a) on risk of myocardial infarction and large-artery IS were comparable in East Asian and European individuals, suggesting that people with either ancestry could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.
Article Details
Authors (162)
Robin G. Walters
Michael Hill
Iona Y. Millwood
Derrick A. Bennett
Paul Sherliker
Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, UK (R. Clarke, N.W., K.L., R.G.W., M.H., C.K., I.Y.M., D.A.B., D.A., L.Y., Y.C., H.D., P.S., X.Y., R. Collins, Z.C. S.P.).
Santica Marcovina
Medpace Reference Laboratories, Cincinnati, OH (S.M.).
Sarah Parish
Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, UK (R. Clarke, N.W., K.L., R.G.W., M.H., C.K., I.Y.M., D.A.B., D.A., L.Y., Y.C., H.D., P.S., X.Y., R. Collins, Z.C. S.P.).
Junshi Chen
Rory Collins
Liming Li
Richard Peto
Daniel Avery
Maxim Barnard
Derrick Bennett
Ruth Boxall
Ka Hung Chan
Yiping Chen
Zhengming Chen
Charlotte Clarke
Jonathan Clarke
Robert Clarke
Huaidong Du
Ahmed Edris Mohamed
Hannah Fry
Simon Gilbert
Pek Kei Im
Andri Iona
Maria Kakkoura
Christiana Kartsonaki
Kshitij Kolhe
Hubert Lam
Kuang Lin
James Liu
Mohsen Mazidi
Iona Millwood
Sam Morris
Qunhua Nie
Alfred Pozarickij
Maryam Rahmati
Paul Ryder
Dan Schmidt
Becky Stevens
Iain Turnbull
Robin Walters
Baihan Wang
Lin Wang
Neil Wright
Ling Yang
Xiaoming Yang
Department of Pathology, Microbiology and Immunology
Pang Yao
Xiao Han
Can Hou
Qingmei Xia
Chao Liu
Jun Lv
Pei Pei
Dianjianyi Sun
Canqing Yu
Lang Pan
Zengchang Pang
Ruqin Gao
Shanpeng Li
Haiping Duan
Shaojie Wang
Yongmei Liu
Division of Cardiology, Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.
Ranran Du
Yajing Zang
Liang Cheng
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices
Xiaocao Tian
Hua Zhang
Yaoming Zhai
Feng Ning
Xiaohui Sun
Feifei Li
State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-environmental Sciences
Silu Lv
Junzheng Wang
Wei Hou
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Wei Sun
Shichun Yan
Xiaoming Cui
Chi Wang
Zhenyuan Wu
Yanjie Li
Quan Kang
Huiming Luo
Tingting Ou
Xiangyang Zheng
Zhendong Guo
Shukuan Wu
Yilei Li
Huimei Li
Ming Wu
Yonglin Zhou
Jinyi Zhou
Ran Tao
Jie Yang
Jian Su
School of Chemistry and Chemical Engineering
Fang Liu
Jun Zhang
Yihe Hu
Yan Lu
Liangcai Ma
Aiyu Tang
Shuo Zhang
Jianrong Jin
Jingchao Liu
Mei Lin
Zhenzhen Lu
Lifang Zhou
Changping Xie
Jian Lan
State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry
Tingping Zhu
Yun Liu
Liuping Wei
Liyuan Zhou
Ningyu Chen
Yulu Qin
Sisi Wang
School of Engineering
Xianping Wu
Ningmei Zhang
Xiaoyu Chang
School of Pharmaceutical Sciences, State key laboratory of antiviral drugs
Mingqiang Yuan
Xia Wu
Tufts Medicine Myeloma and Amyloid Program Tufts Medical Center Boston Massachusetts USA
Xiaofang Chen
Wei Jiang
Jiaqiu Liu
Qiang Sun
Faqing Chen
Xiaolan Ren
Caixia Dong
Hui Zhang
The Fourth Hospital of Hebei Medical University Shijiazhuang China
Enke Mao
Xiaoping Wang
Neutron Scattering Division
Tao Wang
Xi Zhang
Kai Kang
Shixian Feng
Huizi Tian
Lei Fan
Xiaolin Li
Energy and Environmental Directorate, Pacific Northwest National Laboratory
Huarong Sun
Pan He
College of Chemistry, Key Laboratory of Green Chemistry and Technology, Ministry of Education
Xukui Zhang
Min Yu
Ruying Hu
Hao Wang
Division of Quantitative Sciences, Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA
Xiaoyi Zhang
Yuan Cao
Kaixu Xie
Lingli Chen
Dun Shen
Xiaojun Li
Donghui Jin
Li Yin
Vir Biotechnology Inc.
Huilin Liu
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
Zhongxi Fu
Xin Xu
Hao Zhang
Jianwei Chen
Yuan Peng
Libo Zhang
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
Chan Qu