Relationship of Soluble Interleukin-6 Receptors With Asthma: A Mendelian Randomization Study

Frontiers in Medicine

article

Yoshihiko Raita¹  Zhaozhong Zhu¹  Carlos A. Camargo, Jr.¹  Robert J. Freishtat²  Debby Ngo⁵  Liming Liang⁶  Kohei Hasegawa¹ 

[1] Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, United States;Division of Emergency Medicine, Children's National Hospital, United States;Department of Pediatrics, George Washington University School of Medicine and Health Sciences, United States;Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, United States;Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, United States;Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, United States;Department of Biostatistics, Harvard T.H. Chan School of Public Health, United States

关键词: interleukin-6;    soluble interleukin-6 receptor;    trans-signaling pathway;    asthma;    Mendelian randomization;    GWAS;    UK Biobank;   

DOI  :  10.3389/fmed.2021.665057

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Purpose: Emerging evidence suggests a potential role of interleukin-6 pathways—trans-signaling with soluble interleukin-6 receptors—in the asthma pathobiology. Despite the evidence for their associations with asthma, the causal role of soluble interleukin-6 receptors remains uncertain. We investigated the relations of soluble interleukin-6 receptors with asthma and its major phenotypes. Methods: We conducted a two-sample Mendelian randomization study. As genetic instruments, we selected 33 independent cis -acting variants strongly associated with the level of plasma soluble interleukin-6 receptor in the INTERVAL study. To investigate the association of variants with asthma and its phenotypes, we used genome-wide association study data from the UK Biobank. We combined variant-specific causal estimates by the inverse-variance weighted method for each outcome. Results: Genetically-instrumented soluble interleukin-6 receptor level was associated with a significantly higher risk of overall asthma (OR per one standard deviation increment in inverse-rank normalized soluble interleukin-6 receptor level, 1.02; 95%CI, 1.01–1.03; P = 0.004). Sensitivity analyses demonstrated consistent results and indicated no directional pleiotropy—e.g., MR-Egger (OR, 1.03; 95%CI, 1.01–1.05; P = 0.002; P intercept =0.37). In the stratified analysis, the significant association persisted across asthma phenotypes—e.g., childhood asthma (OR, 1.05; 95%CI, 1.02–1.08; P < 0.001) and obese asthma (OR, 1.02; 95%CI 1.01–1.03; P = 0.007). Sensitivity analysis using 16 variants selected with different thresholds also demonstrated significant associations with overall asthma and its phenotypes. Conclusion: Genetically-instrumented soluble interleukin-6 receptor level was causally associated with modestly but significantly higher risks of asthma and its phenotypes. Our observations support further investigations into identifying specific endotypes in which interleukin-6 pathways may play major roles.

【 授权许可】

CC BY