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

Yoshihiko Raita; Zhaozhong Zhu; Carlos A Camargo Jr; Robert J Freishtat; Debby Ngo; Liming Liang; Kohei Hasegawa

doi:10.3389/fmed.2021.665057

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

Front Med (Lausanne). 2021 Apr 12:8:665057. doi: 10.3389/fmed.2021.665057. eCollection 2021.

Authors

Yoshihiko Raita¹, Zhaozhong Zhu¹, Carlos A Camargo Jr¹, Robert J Freishtat^{2

3

4}, Debby Ngo⁵, Liming Liang^{6

7}, Kohei Hasegawa¹

Affiliations

¹ Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
² Division of Emergency Medicine, Children's National Hospital, Washington, DC, United States.
³ Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
⁴ Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
⁵ Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States.
⁶ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States.

Abstract

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.

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

Abstract

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