COVID-19 research

Gene: IFITM3

Green List (high evidence)

Mode of inheritance
Unknown

Publications

• 20064371
• 27384652
• 22446628
• 23361009
• 25942469

Green List (high evidence)

Fair candidate gene

Created: 7 May 2020, 2:09 p.m. | Last Modified: 7 May 2020, 2:09 p.m.

Panel Version: 0.203

Green List (high evidence)

IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 20064371 Brass et al. (2009) used a functional genomic screen to identify IFITM3 as an antiviral restriction factor in influenza A H1N1 viral infection. Further characterization showed IFITM3 inhibits the early replication of flaviviruses, including dengue virus and West Nile virus. PMID: 27384652 Gorman et al. (2016) Ifitm3(-/-) mice are more vulnerable to lethal WNV infection than their wildtype littermates, this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. PMID: 22446628 Everitt et al. (2012). Ifitm3(-/-) mice display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, a phenotype which may be rescued by the re-introduction of Ifitm3. PMID: 22446628 Everitt et al. (2012). A statistically significant number of hospitalized with seasonal or pandemic influenza H1N1/09 viruses subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C). This SNP alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. PMID: 23361009 Zhang et al. (2013) In a Han Chinese patient population, the rs12252-C, CC genotype was found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. The CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. PMID: 25942469 Yang et al. (2015) performed meta-analysis of four studies consisting of 445 cases and 4180 controls. A significant association between a minor IFITM3 allele (SNP rs12252-C) with severe influenza susceptibility, but not in mild influenza subjects, in both UK Caucasians and Han Chinese population was confirmed. The rs12252-C allele causes a 23.7% higher chance of infection and also constitutes a risk factor for more severe influenza.

Created: 11 Jun 2020, 6:10 p.m. | Last Modified: 12 Jun 2020, 10:37 a.m.

Panel Version: 1.29

rs12252-CC is enriched amonst hospitalised cases with influenza infections. Functional studies showed that rs12252-CC lymphoblastoid cell lines were more susceptibile to infection than TT cell lines and this was correlated with lower levels of IFITM3 protein expression as compared to the majority (TT) variant cells (PMID 22446628). In addition, a Ifitm3 knockout mouse displayed fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus (PMID 22446628;18505827). PMID 32348495 reports 35% of hospilalised patients were homozygous for rs12252-CC, plus CC vs CT/TT was associated with disease severity (p = 0.00093; OR = 6.37) and 2/3 of the patients who died were rs12252-CC. 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 (https://www.internationalgenome.org/1000-genomes-browsers)

Created: 4 May 2020, 3:17 p.m. | Last Modified: 4 May 2020, 3:17 p.m.

Panel Version: 0.176

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
{Influenza, severe, susceptibility to} 614680

Publications

• 22446628
• 18505827
• 32348495

Comment on list classification: PMID: 32348495 reports that individuals who are homozygous for the C allele of rs12252 SNP in IFITM3 is associated with more severe disease in older patients. This SNP is common in Asian populations (MAF reported on dbSNP for East Asians: 0.57; Europeans: 0.0546). This study was condicted in China with 80 patients who were confirmed to be positive for COVID-19.

PMID: 23361009 found that homozygous C allele of rs12252 is in 69% of Chinese patients who were infected with severe pandemic influenza A H1N1/09 virus infection compared with 25% who had mild infection. The homozygous C allele for rs12252 is associated with a 6-fold greater risk for severe infection than CT and TT genotypes.

Based on these studies there is enough evidence to promote this gene to Green status.

Created: 4 May 2020, 8:25 a.m. | Last Modified: 4 May 2020, 8:25 a.m.

Panel Version: 0.173