Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study

Disease areas:

• brain
• heart and blood vessels

Last updated:

19 November 2025

Author(s):

Robert Clarke, Neil Wright, Kuang Lin, Canqing Yu, Robin G. Walters, Jun Lv, Michael Hill, Christiana Kartsonaki, Iona Y. Millwood, Derrick A. Bennett, Daniel Avery, Ling Yang, Yiping Chen, Huaidong Du, Paul Sherliker, Xiaoming Yang, Dianjianyi Sun, Liming Li, Chan Qu, Santica Marcovina, Rory Collins, Zhengming Chen, Sarah Parish, Junshi Chen, Zhengming Chen, Robert Clarke, Rory Collins, Liming Li, Jun Lv, Richard Peto, Robin Walters, 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, 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, Ranran Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang, Yaoming Zhai, Feng Ning, Xiaohui Sun, Feifei Li, Silu Lv, Junzheng Wang, Wei Hou, 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, 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, Tingping Zhu, Yun Liu, Liuping Wei, Liyuan Zhou, Ningyu Chen, Yulu Qin, Sisi Wang, Xianping Wu, Ningmei Zhang, Xiaofang Chen, Xiaoyu Chang, Mingqiang Yuan, Xia Wu, Xiaofang Chen, Wei Jiang, Jiaqiu Liu, Qiang Sun, Faqing Chen, Xiaolan Ren, Caixia Dong, Hui Zhang, Enke Mao, Xiaoping Wang, Tao Wang, Xi zhang, Kai Kang, Shixian Feng, Huizi Tian, Lei Fan, XiaoLin Li, Huarong Sun, Pan He, Xukui Zhang, Min Yu, Ruying Hu, Hao Wang, Xiaoyi Zhang, Yuan Cao, Kaixu Xie, Lingli Chen, Dun Shen, Xiaojun Li, Donghui Jin, Li Yin, Huilin Liu, Zhongxi Fu, Xin Xu, Hao Zhang, Jianwei Chen, Yuan Peng, Libo Zhang, Chan Qu

Publish date:

29 April 2025

Journal:

Circulation

PubMed ID:

40297899

DOI:

10.1161/circulationaha.124.072086

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.