Chronic respiratory diseases (CRDs), featuring the constant destruction to the respiratory tract and other lung structures, have gradually become a member of the prevalent causes of morbidity and mortality globally. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, sarcoidosis, and bronchiectasis are universally recognized as several most significant CRDs from a prevalence standpoint [1]. They not only greatly result in the continuously increasing global health burden but also pose a huge danger to public health throughout all nations, particularly in developing countries as well as low-income regions [2]. It is statistically reported that during the years from 1990 to 2017 worldwide, the total number of people suffering from CRDs has increased by 39.8 % since 1990 and to nearly 545 million in 2017 [3], and that of individuals dying from CRDs has surged by 18.0 % from 3.32 million in 1990 to 3.91 million in 2017 [4].

Despite the not completely understood etiology and pathogenesis of CRDs, hereditary and environmental factors are crucial drivers in their initiation and exacerbation. The relevant risk factors mainly include environmental pollution, occupational exposure, smoking, alcohol assumption, a high body mass index, etc [2], [4]. Cytokine-induced chronic inflammation is a remarkable characteristic of CRDs, and patients with CRDs can benefit from cytokine-targeted anti-inflammatory therapies [5], [6]. Additionally, accumulative evidence indicates that circulating levels of inflammatory cytokines are intimately related to risk of CRDs. It was reported that interleukin-17 (IL-17)-driven inflammation can facilitate the progression of multiple CRDs, such as COPD, asthma, cystic fibrosis, and lung cancer [7]. Similarly, type 2 cytokines (e.g. IL-4, -5, and -13) were found in correlation with asthma via promoting mucus oversecretion, airway eosinophilia, bronchial hypersensitivity and IgE synthesis [8]. Moreover, most IL-17 isoforms play significant roles in regulating chronic inflammation by innate and adaptive immunity, and overexpression of IL-17 leads to multiple pathological consequences, especially the occurrence and progression of IPF [9]. Nevertheless, traditional observational studies could be affected by multiple biases from reverse causation and confounding variables [10]. Accordingly, it is a necessity to determine whether these alterations in systemic inflammatory regulators are causative of the inflammatory progression of CRDs or they merely function as consequences of an inflammatory response, given the ambiguity regarding the latent causative role of certain cytokines in determining CRDs.

Mendelian randomization (MR), an emerging statistical approach, has a notable edge in inferring causal relationships and mimicking a randomized controlled trial via randomly allocating genetic variants during observation [11]. Specifically, single nucleotide polymorphisms (SNPs) are employed in MR as instrumental variables (IVs) to mimic and infer whether a risk factor has a causal effect on a health outcome, thus eliminating biases from reverse causation and confounding factors [12]. MR has been broadly used to reveal the causation between systemic inflammatory regulators and a variety of diseases, including proliferative diabetic retinopathy [13], polycystic ovary syndrome [14], acute-on-chronic liver failure [15], and Alzheimer's disease [16]. To date, no research has yet comprehensively investigated the causal influences of systemic inflammatory regulators on CRDs.

Herein, a comprehensive two-sample MR study was conducted utilizing the largest public genome-wide association study (GWAS) database to explore the associations between 41 systemic inflammatory regulators and 5 common CRDs, including IPF, COPD, asthma, bronchiectasis, and sarcoidosis. Moreover, our findings were also strengthened by performing sensitivity, pleiotropy, and heterogeneity analyses. Our study focuses on the underlying role of systemic inflammatory regulators in the etiology of CRDs and possibly hints several novel circulating biomarkers for the prediction or treatment of these torturous diseases.