Affiliation:
1. Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine
2. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
3. The Second School of Clinical Medicine, Southern Medical University
4. School of Public Health and Women's Hospital, Zhejiang University School of Medicine
5. Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University
6. Centre for Global Health, Usher Institute, University of Edinburgh
7. Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh
Abstract
Background:Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and COVID-19 risk.Methods:Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1, and the risk of COVID-19 (susceptibility, hospitalization, and severity) using genome-wide association study (GWAS) summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test were conducted as sensitivity analyses.Results:Higher genetically predicted IGF-1 levels have nominally significant association with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval [CI], 0.61–0.97, p=0.027) for COVID-19 susceptibility, 0.62 (95% CI: 0.25–0.51, p=0.018) for COVID-19 hospitalization, and 0.85 (95% CI: 0.52–1.38, p=0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, and SHBG are associated with the risk of COVID-19 susceptibility, hospitalization, and severity in either overall or sex-stratified TSMR analysis.Conclusions:Our study indicated that genetically predicted high IGF-1 levels were associated with decrease the risk of COVID-19 susceptibility and hospitalization, but these associations did not survive the Bonferroni correction of multiple testing. Further studies are needed to validate the findings and explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk.Funding:We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).
Funder
Natural Science Foundation of Zhejiang Province
Cancer Research UK
Swedish Cancer Foundation
Swedish Research Council
Swedish Heart Lung Foundation
Science Fund for Distinguished Young Scholars of Zhejiang Province
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Reference55 articles.
1. IGF1 and IGFBP3 in acute respiratory distress syndrome;Ahasic;European Journal of Endocrinology,2012
2. Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER) -positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells;Bartucci;Cancer Research,2001
3. Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression;Bowden;International Journal of Epidemiology,2015
4. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator;Bowden;Genetic Epidemiology,2016
5. Mendelian Randomization