Abstract
Background
Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity.
Aim
To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity.
Methods
This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection.
Results
In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele.
Conclusions
In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7 MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.
Contributor Information
Junghee J Shin, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Wei Fan, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Jennefer Par-Young, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Marta Piecychna, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Lin Leng, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Kavita Israni-Winger, Department of Medicine, Department of Immunobiology, New Haven, CT, USA.
Hua Qing, Department of Medicine, Department of Immunobiology, New Haven, CT, USA.
Jianlei Gu, Department of Pathology, New Haven, CT, USA.
Hongyu Zhao, Department of Pathology, New Haven, CT, USA.
Wade L Schulz, Department of Medicine, Department of Immunobiology, New Haven, CT, USA.
Serhan Unlu, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
John Kuster, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Grant Young, Cardiology, New Haven, CT, USA.
Jian Liu, Department of Pathology, New Haven, CT, USA.
Albert I Ko, Department of Pathology, New Haven, CT, USA.
Alvaro Baeza Garcia, Inserm 1231 Lipids, Nutrition Cancer, Dijon, France.
Maor Sauler, Pulmonary, Critical Care, and Sleep Medicine, New Haven, CT, USA.
Adam V Wisnewski, Department of Laboratory Medicine, New Haven, CT, USA.
Lawrence Young, Cardiology, New Haven, CT, USA.
Antonio Orduña, Microbiology Service. Hospital Clínico Universtario. Valladolid. Spain.
Andrew Wang, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA; Department of Medicine, Department of Immunobiology, New Haven, CT, USA.
Ocskay Klementina, Universidad de Valladolid, Valladolid, Spain; University of Pécs, Pécs, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest Hungary.
Antonio Blesa Garcia, Mucosal Immunology Lab. Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC. Valladolid. Spain.
Peter Hegyi, Universidad de Valladolid, Valladolid, Spain; University of Pécs, Pécs, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest Hungary; Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Michelle E Armstrong, Trinity College Dublin, Dublin, Ireland.
Patrick Mitchell, Trinity College Dublin, Dublin, Ireland.
David Bernardo Ordiz, Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary; Centro de Investigaciones Biomédicas en Red de Enfermedades infecciosas (CIBERinfec). Madrid. Spain.
András Garami, Universidad de Valladolid, Valladolid, Spain; University of Pécs, Pécs, Hungary. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
Insoo Kang, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA.
Richard Bucala, Sections of Rheumatology, Allergy and Immunology, New Haven, CT, USA; Department of Pathology, New Haven, CT, USA; Yale Schools of Medicine and Public Health, New Haven, CT, USA.
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