The Association Of NAFLD And Autoimmune Diseases With COVID-19 Severe Illness And Death

An acute respiratory infectious disease（Corona Virus Disease 2019,COVID-19）caused by Severe Acute Respiratory Syndrome Coronavirus 2（SARS-Co V-2）has spread rapidly worldwide since 2019.COVID-19 severe illness and death（COVID-19-SD）is a hazard to public health and a burden on the health service system.Age,male,and endocrine and metabolic diseases such as obesity and type 2 diabetes mellitus（T2D）are independent risk factors for COVID-19-SD.However,whether nonalcoholic fatty liver disease（NAFLD）and autoimmune diseases will increase the risk of COVID-19-SD remains controversial.This study will combine observational and Mendelian randomization（MR）studies to comprehensively and deeply analyze the association between NAFLD and autoimmune diseases and COVID-19-SD.The subjects used in the observational study were 8,267 SARS-Co V-2 positive and unrelated European populations（including 556 COVID-19-SD）from the UK Biobank（UKB）cohort;autoimmune diseases involved in the study included type 1 diabetes mellitus（T1D）,rheumatoid arthritis（RA）,multiple sclerosis（MS）,systemic lupus erythematosus（SLE）,inflammatory bowel disease（IBD）,and celiac disease（Ce D）.To reveal the association between NAFLD,autoimmune diseases（including the above six diseases）,and each autoimmune disease and COVID-19-SD,respectively,we first detected the correlation between the three and COVID-19-SD using the univariate Logistic regression analysis.Then we adjusted age,sex,body mass index（BMI）,T2D,atherosclerosis cardiovascular disease（ASCVD）,cirrhosis,and systolic blood pressure（only applied to NAFLD）in the multivariant Logistic regression analysis to further reveal the correlation between the three and COVID-19-SD after eliminating the effect of these risk factors.Finally,this study analyzed the causal relationship between NAFLD,autoimmune diseases,and COVID-19-SD by MR study using the currently available genome-wide association analysis（GWAS）.The results of the univariate Logistic regression analysis showed that NAFLD(OR=3.06,P=1.07×10^-06)was positively correlated with COVID-19-SD;autoimmune diseases(OR=2.19,P=2.14×10^-08)and their T1D(OR=3.30,P=1.22×10^-05),RA(OR=2.80,P=4.90×10^-07),and MS(OR=2.99,P=1.53×10^-02)were positively correlated with COVID-19-SD,while no significant correlation between SLE,IBD,and Ce D and COVID-19-SD（P>0.05）.The multivariate Logistic regression analysis showed no significant correlation between NAFLD and COVID-19-SD（OR=1.57,P=0.09）;autoimmune diseases(OR=1.44,P=1.81×10^-02)and their RA(OR=1.88,P=4.20×10^-03),and MS(OR=2.79,P=4.79×10^-02)were positively correlated with COVID-19-SD,while there was no significant correlation between T1D and COVID-19-SD（P>0.05）.The MR findings showed no causal relationship between NAFLD and COVID-19-SD（P>0.05）;MS in autoimmune diseases was positively causal associated with COVID-19-SD(OR=1.05,P=5.02×10^-04),while there was no causal relationship between T1D,RA,SLE,IBD,and Ce D and COVID-19-SD（P>0.05）.The above findings showed that NAFLD was not an independent risk factor for COVID-19-SD,there was no causal relationship between them;autoimmune diseases and their RA and MS were independent risk factors for COVID-19-SD and a positive causal relationship between MS and COVID-19-SD.Based on the above findings,we concluded as follows:（1）NAFLD may not increase the risk of COVID-19-SD.（2）Patients with autoimmune diseases are at high risk for COVID-19-SD,and RA and MS may be the main risk factors for COVID-19-SD,but the contribution of other autoimmune diseases cannot be completely excluded.（3）The findings of observational and MR studies may differ due to unknown confounders and insufficient statistical power.In the face of emerging diseases such as COVID-19,we should interpret the differential findings obtained from the two analyses with caution.