The influence of IFITM3 polymorphisms on susceptibility to SARS-CoV-2 infection and severity of COVID-19

Abstract

Background and aims The interferon-induced transmembrane protein 3 (IFITM3) plays an important role in the adaptive and innate immune response by inhibiting viral membrane hemifusion between the host and viral cell cytoplasm. Single nucleotide polymorphisms (SNPs) in the gene IFITM3 have been associated with susceptibility and severity of influenza or other viral infections. We aimed to analyze the role of SNPs in the gene IFITM3 in SARS-CoV-2 infection. Methods We performed genotyping of the SNPs rs12252 and rs34481144 in the gene IFITM3 in 239 SARS–CoV–2–positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. Results SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics. Neither IFITM3 rs12252 nor rs34481144 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. Interestingly, we observed the putative deleterious rs12252 CC genotype only in SARS-CoV-2-positive patients (N = 2). Also, we found a non-significant higher frequency of rs34481144 A-allele carriers in the patients with 'serious' COVID-19. Conclusions In summary, we could not confirm the recently reported influence of polymorphisms in the gene IFITM3 on SARS-CoV-2 infection risk or severity of COVID-19 in a German cohort. Additional studies are needed to clarify the influence of the rs12252 CC genotype on SARS–CoV–2 infection risk and the rs34481144 A-allele on course of COVID-19.

Host polymorphisms and COVID-19 infection

“…The A allele of this promoter SNP shows decreased IFITM3 mRNA and protein levels, diminishing the antiviral defense capacities of IFITM3 [87] . In a case–control study in Caucasians, there was no difference in the frequency of rs34481144 alleles or genotypes in SARS-CoV-2-positive ( n = 239) compared to SARS-CoV-2-negative ( n = 239) patients [86] . In contrast to the previous finding, a significant correlation and a striking agreement was observed between the reported standardized mortality ratios and the frequency of the combined haplotype of rs12252 and rs34481144 of ethnic groups in England.…”

“…However, in a German cohort study, no association between IFITIM3 rs12252 and SARS-CoV-2 infection susceptibility or COVID-19 severity was found. The A-allele of a second SNP (rs34481144, c.-22-64G > A) has the highest MAF in Europeans (0.46) and a very low MAF in East Asians [86] . The A allele of this promoter SNP shows decreased IFITM3 mRNA and protein levels, diminishing the antiviral defense capacities of IFITM3 [87] .…”

The Interferon-Induced Transmembrane Protein 3 -rs12252 Allele May Predict COVID-19 Severity Among Ethnic Minorities

“…The IFITM3-rs12252 variant was also associated with hospitalization and mortality in a study of 880 patients from Saudi Arabia, and they had a lower level of Interferon Gamma (Alghamdi et al, 2021 ). In contrast, a study from Germany did not find an association with infection risk or severity but suggested that this allele may be important for predicting infection risk (Schönfelder et al, 2021 ).…”

Genome interaction of the virus and the host genes and non-coding RNAs in SARS-CoV-2 infection

“… Qian et al, 2021 CCR5 j Analysis of a new mutation CCR5Delta 32 in 416 SARS-CoV-2-positive infection survivors (164 asymptomatic and 252 symptomatic) - Association of the highest number of CCR5Delta32 carriers in SARS-CoV-2-positive/COVID-19-asymptomatic subjects when compared to the SARS-CoV-2-positive/COVID-19-symptomatic patients- CCR5Delta32 I/D polymorphism may have the potential to predict the severity of SARS-CoV-2 infection Hubaceck et al, 2021 IFIH1 k Analysis of the IFIH1 polymorphism, rs1990760 (C>T; aaA946T) in the epidemiology of SARS-CoV-2 infection in different populations - T allele–carrying individuals may be more resistant to SARS-CoV-2- Africans or African Americans with low allelic frequency of rs1990760 (T allele) are more vulnerable-risk groups than Caucasians and Indians Maiti et al, 2020 IFITM3 l Analysis of the SNPs rs12252 and rs34481144 in the gene IFITM3 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients - Neither IFITM3 rs12252 nor rs34481144 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19- CAT plays a crucial intermediary role in binding effectiveness of ACE2 , thereby affecting the susceptibility to COVID-19. Schönfelder et al, 2021 a ACE2 : Angiotensin I converting enzyme 2; b CTSB : Cathepsin B; c CTSL : Cathepsin L; d TMPRSS2 : Transmembrane serine protease 2; e ACE1 : Angiotensin I converting enzyme; f CD26 : dipeptidil peptidase IV (DPPIV/CD26); g HLA : Human leukocyte antigen; h CAT : catalase; i EHF : ETS homologous factor; j CCR5: CC chemokine receptor 5; k IFIH1 : Interferon-induced helicase 1; l IFITM3 : Interferon-induced transmembrane protein 3; m ChinaMAP: China metabolic analytics project (ChinaMAP); n 1KGB: 1000 Genomes Project; o HapMap3: International haplotype map project 3; p eQTL: Expression quantitative trait loci ; q MHC: Major histocompatibility complex. …”

“…Polymorphisms in other genes unrelated to ACE1/2 and TMPRSS2 have been associated with susceptibility to SARS-CoV-2 infection, including polymorphisms in the HLA (Lorente et al, 2020; Nguyen et al, 2020 , Tomita et al, 2020 ) and ABO blood group ( Ellinghaus et al, 2020 , Zhao et al, 2020 ) genes as well as in other genes ( Qian et al, 2021 ; Hubaceck et al, 2021; Maiti, 2020 , Schönfelder et al, 2021 ), such as the IF1H1 gene (rs1990760; (C>T)), a cytoplasmic viral RNA receptor that activates interferon signaling ( Qian et al, 2021 ) ( Table 2 ). In a genome-wide association study (GWAS), Ellinghaus et al (2020) found that the following two loci associated with COVID-19 induce respiratory failure: the rs11385942 insertion–deletion at locus 3p21.31 (containing six genes: SLC6A20, LZTFL1, FYCO1, CXCR6, XCR1, and CCR9 ) and the rs657152 A or C SNP at locus 9q34.2 (which determines the ABO blood groups).…”