Causal relationship between asthma-related diseases and the risk of COVID-19: A 2-sample mendelian randomization study

We read with interest the study recently published by Skevaki et al1Skevaki C. Chinthrajah R.S. Fomina D. Rohde G. Cao S. He Z. et al.Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: a global perspective.J Allergy Clin Immunol. 2023; 151: 110-117Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar in the Journal of Allergy and Clinical Immunology. Skevaki et al1Skevaki C. Chinthrajah R.S. Fomina D. Rohde G. Cao S. He Z. et al.Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: a global perspective.J Allergy Clin Immunol. 2023; 151: 110-117Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar found that the differences in risk associated with coronavirus disease 2019 (COVID-19) that are observed in patients with asthma are associated with different prevalence of underlying comorbidities, particularly, chronic obstructive pulmonary disease (COPD). However, inconsistent associations between asthma and COVID-19 disease have been observed in epidemiology studies.2Ren J. Pang W. Luo Y. Cheng D. Qiu K. Rao Y. et al.Impact of allergic rhinitis and asthma on COVID-19 infection, hospitalization, and mortality.J Allergy Clin Immunol Pract. 2022; 10: 124-133Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,3Bloom C.I. Cullinan P. Wedzicha J.A. Asthma phenotypes and COVID-19 risk: a population-based observational study.Am J Respir Crit Care Med. 2022; 205: 36-45Crossref PubMed Scopus (31) Google Scholar The causality of the association between asthma and COVID-19 has not been established. Because of confounding, inferring causal effects only from observational studies is difficult. Mendelian randomization (MR) analysis is widely used to assess the presence of causal relationships between genetic variants and selected outcome, and it is not prone to confounding biases and reverse causality if certain assumptions are satisfied. Here, we have leveraged data from large-scale genome-wide association studies (GWASs) to verify the findings of Skevaki et al1Skevaki C. Chinthrajah R.S. Fomina D. Rohde G. Cao S. He Z. et al.Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: a global perspective.J Allergy Clin Immunol. 2023; 151: 110-117Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar and apply them in 2-sample MR analysis to investigate the causality between asthma and COVID-19 in European samples. MR was conducted with inverse variance–weighted single-nucleotide polymorphisms with P values less than 10−8 as instrumental variables. The linkage disequilibrium threshold was set to an r2 value of 0.001 within a distance of 10,000 kb. We used the exposure GWAS summary data from the Integrative Epidemiology Unit OpenGWAS project (https://www.mrbase.org/), which was developed at the Medical Research Council Integrative Epidemiology Unit at the University of Bristol4Hemani G. Zheng J. Elsworth B. Wade K.H. Haberland V. Baird D. et al.The MR-Base platform supports systematic causal inference across the human phenome.Elife. 2018; 7e34408Crossref PubMed Scopus (2064) Google Scholar and included information on asthma (ukb-b-18113; n = 462,933), eosinophil counts (ieu-b-33; n = 563,946), asthma and/or COPD (finn-b-J10_ASTHMACOPDKELA; n = 208,167), and allergic rhinitis or eczema (ukb-a-447; n = 336,782). Outcome genetic association estimates for COVID-19 were obtained from release 7 (April 8, 2022) of the COVID-19 Host Genetics Initiative GWAS.5Covid 19 Host Genetics IThe COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic.Eur J Hum Genet. 2020; 28: 715-718Crossref PubMed Scopus (436) Google Scholar Three COVID-19 traits were selected: COVID versus population (2,597,856 samples), hospitalization due to COVID versus population (2,095,324 samples), and having very severe respiratory-confirmed COVID versus population (1,086,211 samples). All of the summary statistical data are publicly available and were obtained with the consent and ethical approval of the relevant participants. The MR analyses showed that asthma was associated with decreased risk for either developing severe COVID-19 (odds ratio [OR] = 0.46; 95% CI = 0.21-0.99; P = .047) or being hospitalized because of COVID-19 (OR = 0.58; 95% CI = 0.34-0.90; P = .047) but not with having COVID-19 infection (P = .08). No results supported the idea that eosinophil counts and COPD comorbidities affect COVID-19 cases. MR analyses showed that allergic rhinitis or eczema could lower the risk of being hospitalized with COVID-19 (OR = 0.71; 95% CI = 0.53-0.93; P = .015) and having severe COVID-19 (OR = 0.66; 95% CI = 0.44-0.99; P = .049) but not with COVID-19 infection (P = .26) (Table 1).Table IMendelian randomization analysis estimate of associations between asthma-related diseases and COVID-19 diseases with use of the inverse variance–weighted methodExposureCOVID-19Hospitalized COVID-19Severe COVID-19SNPsOR (95% CI)P valueSNPsOR (95% CI)P valueSNPsOR (95% CI)P valueAsthma970.82 (0.66-1.02).08970.58 (0.34-0.90).047950.46 (0.21-0.99).047Eosinophil count4351.00 (0.98-1.02).684350.90 (0.95-1.05).904301.06 (0.98-1.15).09Allergic rhinitis or eczema1010.92 (0.80-1.06).261000.71 (0.53-0.93).015980.66 (0.44-0.99).049Asthma/COPD231.00 (0.96-1.04).81230.95 (0.86-1.05).35230.96 (0.81-1.14).70Boldface indicates statistical significance.SNP, Single-nucleotide polymorphism. Open table in a new tab Boldface indicates statistical significance. SNP, Single-nucleotide polymorphism. In the study, we demonstrated that asthma or allergic rhinitis or eczema may be a causal protective factor for the incidence of severe COVID-19 and hospitalization due to COVID-19 but did not reduce the risk of COVID-19 infection. This suggested that allergic diseases may be of great relevance to reduction of the risk of development of severe COVID-19 and being hospitalized with COVID-19 infection. In addition, we found no association between both eosinophil count levels and COPD comorbidities and risk of COVID-19 diseases in European samples. However, whether these conclusions can be generalized to other populations needs to be studied further with larger summary data. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. Data availability: The data sets presented in this study can be found in online repositories. The names of the repository/repositories and identifiers can be found in this article. We acknowledge the efforts of the Medical Research Council Integrative Epidemiology Unit in providing high-quality GWASs data in the MR-Base platform for researchers. Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: A global perspectiveJournal of Allergy and Clinical ImmunologyVol. 151Issue 1PreviewThe global epidemiology of asthma among patients with coronavirus disease 2019 (COVID-19) presents striking geographic differences, defining prevalence zones of high and low co-occurrence of asthma and COVID-19. Full-Text PDF