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.To determine
associations of common functional polymorphisms in MIF with symptomatic COVID-19 or
its severity.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.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.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.
