Genetic Evidence on the Association of Interleukin (IL)-1-Mediated Chronic Inflammation with Airflow Obstruction: A Mendelian Randomization Study

Preclinical studies suggest interleukin (IL)-1α/β is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, recent trials of anti-IL-1 therapies showed limited benefit for COPD. To clarify, we primarily examined total and direct effects of IL-1 and its receptors/coreceptors/receptor antagonists (IL-1/IL-1Rs) on airflow obstruction (AO) using Mendelian randomization (MR), and secondarily explored reverse causation using bidirectional MR. We selected independent cis protein quantitative trait loci (cis-pQTLs) as genetic instruments for IL-1/IL-1Rs from two proteomic genome-wide association studies (n = 11,594) of European ancestry (mean age ∼47 years). We applied those cis-pQTLs to the International COPD Genetics Consortium (n = 15,256 cases, 47,936 controls) of ∼81.9% European descent (∼57 years). No IL-1/IL-1Rs were significantly associated with AO after correction for multiple testing. However, a higher genetically predicted IL-1 receptor antagonist (IL-1Ra) was nominally associated with a 20% reduction in AO risk using univariable MR, with a larger direct effect (∼31%, i.e. not via IL-1α/β) using multivariable MR. Furthermore, higher total IL-18 binding protein (IL-18BP) was nominally associated with lower AO. Nominal total effects were also noted for higher IL-1α with lower AO and higher IL-1R1 with higher AO. Higher IL-1Ra and IL-18BP might have a role in preventing AO, but need to be contextualized. Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1955848.