MIF is a common genetic determinant of COVID-19 symptomatic infection and severity
J J Shin1, W Fan1, J Par-Young1
1Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA.
Background:
Genetic predisposition to coronavirus disease 2019 (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 USA, 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%, odds ratio (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 CATT7MIF 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 the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection.
Insights
The macrophage migration inhibitory factor (MIF) CATT7 allele is linked to lower COVID-19 infection risk but higher hospitalization rates. This common genetic variant influences disease progression in SARS-CoV-2 infections.
Area of Science:
- Immunogenetics
- Infectious Diseases
- Genetics
Background:
- Genetic predisposition influences COVID-19 severity and mortality.
- Cytokines are crucial in various infection phases.
- Investigating macrophage migration inhibitory factor (MIF) polymorphisms for COVID-19 associations.
Purpose of the Study:
- Determine associations between common functional MIF polymorphisms and symptomatic COVID-19.
- Evaluate the link between MIF gene variants and COVID-19 disease severity.
Main Methods:
- Retrospective case-control study of 1171 COVID-19 patients and 637 healthy controls.
- Analysis of MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF, and soluble MIF receptor levels.
- Correlated genetic data with COVID-19 diagnosis, hospitalization, and experimental mouse models.
Main Results:
- Lower frequency of high-expression MIF CATT7 allele in COVID-19 patients vs. controls (11% vs. 19%).
- Higher frequency of MIF CATT7 allele in COVID-19 inpatients vs. outpatients (12% vs. 5%).
- Inpatients showed higher serum MIF levels; CATT7 allele associated with more severe disease in mouse models.
Conclusions:
- The -794 CATT7 MIF allele is linked to reduced susceptibility to symptomatic SARS-CoV-2 infection.
- This allele is also associated with increased disease progression, indicated by hospitalization.
- Findings highlight the role of the high-expression CATT7 MIF allele in different stages of COVID-19.
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