Shi Jikang, Liang Zhuoshuai, Liu Zhantong, Pan Lingfeng, Hu Xinmeng, Tian Yuyang, Jin Huizhen, Liu Yawen, Cheng Yi, Zhang Ming
Department of Clinical Nutrition Peking University Shenzhen Hospital Shenzhen China.
Department of Epidemiology and Biostatistics School of Public Health of Jilin University Changchun China.
J Am Heart Assoc. 2024 Dec 3;13(23):e036202. doi: 10.1161/JAHA.124.036202. Epub 2024 Nov 27.
Smoking is a factor for hypertension. We aim to reveal novel plasma proteins mediating the relationship of smoking with hypertension and identify potential drug targets for hypertension on the basis of Mendelian randomization design.
Data for smoking were selected from the largest genome-wide association study meta-analysis performed by the Genome-Wide Association Study and Sequencing Consortium of Alcohol and Nicotine Use. Data for plasma proteins were selected from the deCODE Health study and the UK Biobank Pharma Proteomics Project. Data for hypertension were extracted from the FinnGen Study. Moreover, proteome-wide Mendelian randomization and colocalization analyses, 2-step Mendelian randomization, and gene function and network prediction, as well as druggability assessment were performed. We finally identified 8 proteins (ANXA4 [annexin A4], DLK1 [protein delta homolog 1], KLB [β-klotho], MMP8 [matrix metallopeptidase 8], PLAT [tissue-type plasminogen activator], POSTN [periostin], SAT2 [thialysine N-ε-acetyltransferase], and IFNLR1 [interferon λ receptor 1]) mediating association of smoking with hypertension. PLAT and IFNLR1 were identified to be involved in the complement and coagulation cascades and the Janus kinase/signal transducer and activator of transcription signaling pathway. ANXA4, KLB, MMP8, PLAT, and IFNLR1 had druggability. Moreover, IFNLR1 had strong evidence of genetic colocalization, because the posterior probability for H4 of IFNLR1 was 91.3%.
This study identified the 8 proteins that mediate causal association between smoking and essential hypertension. Interferon λ receptor agonist targeting IFNLR1 may open a new avenue for treating hypertension. Our discoveries provide new insights into protein pathogenesis of hypertension and to better guide hypertension prevention and treatment among smokers.
吸烟是高血压的一个影响因素。我们旨在揭示介导吸烟与高血压关系的新型血浆蛋白，并基于孟德尔随机化设计确定高血压的潜在药物靶点。
吸烟数据选自酒精和尼古丁使用全基因组关联研究与测序联盟进行的最大规模全基因组关联研究荟萃分析。血浆蛋白数据选自deCODE健康研究和英国生物银行药物蛋白质组学项目。高血压数据取自芬兰基因研究。此外，还进行了全蛋白质组孟德尔随机化和共定位分析、两步孟德尔随机化、基因功能和网络预测以及药物可及性评估。我们最终确定了8种蛋白（膜联蛋白A4、δ-同源蛋白1、β-klotho、基质金属肽酶8、组织型纤溶酶原激活剂、骨膜蛋白、硫赖氨酸N-ε-乙酰转移酶2和干扰素λ受体1）介导吸烟与高血压的关联。组织型纤溶酶原激活剂和干扰素λ受体1被确定参与补体和凝血级联反应以及Janus激酶/信号转导和转录激活因子信号通路。膜联蛋白A4、β-klotho、基质金属肽酶8、组织型纤溶酶原激活剂和干扰素λ受体1具有药物可及性。此外，干扰素λ受体1有很强的基因共定位证据，因为其H4的后验概率为91.3%。
本研究确定了8种介导吸烟与原发性高血压因果关联的蛋白。靶向干扰素λ受体1的干扰素λ受体激动剂可能为治疗高血压开辟一条新途径。我们的发现为高血压的蛋白质发病机制提供了新见解，以更好地指导吸烟者的高血压预防和治疗。
