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There is an urgent unmet need to understand why some people develop severe disease. Heritable differences are known to modulate individual susceptibility to and severity of infectious disease. We hypothesized that a genetic variant of IFITM3 was associated with the severity of COVID-19, specifically the SNP rs12252. This genetic variant is common in Asian populations and homozygosity for the C allele has been associated with influenza severity. IFITM3 encodes an immune effector protein critical to viral restriction and acts to restrict membrane fusion. It is currently unknown whether IFITM3 shows genetic association with the severity of COVID-19.

Mild disease (n=56) was defined as patients with fever, respiratory symptoms and pneumonia from imaging. Patients with severe disease (n=24) were those who in addition developed significant tachypnoea, hypoxia, respiratory failure or other organ failure. The patient cohort was broadly representative of published clinical reports in the outbreak to date in terms of case mix and severity.

To test if the homozygous C-allele carriers associate with the severity of COVID-19, we genotyped the cohort by sequencing a 300bp locus spanning rs12252. Among all hospitalized patients we found that 35% were homozygous for the CC allele (46.25% CT heterozygotes and 18.75% TT homozygotes). We found a significant difference between mild and severe cases adjusting for age on regression analysis, with homozygosity for the C allele (CC vs CT/TT) associated with disease severity (p = 0.00093; OR = 6.37; Table 2). In addition, two of the three patients who died carried the CC genotype. However, the frequency of CC genotype (28.6%) observed in our mild patient groups is similar to general Beijing population (26.2%) according to g1000data base

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