IFITM3, FURIN, ACE1, and TNF-α Genetic Association With COVID-19 Outcomes: Systematic Review and Meta-Analysis

Abstract

Human polymorphisms may contribute to SARS-CoV-2 infection susceptibility and COVID-19 outcomes (asymptomatic presentation, severe COVID-19, death). We aimed to evaluate the association of IFITM3, FURIN, ACE1, and TNF-α genetic variants with both phenotypes using meta-analysis. The bibliographic search was conducted on the PubMed and Scielo databases covering reports published until February 8, 2022. Two independent researchers examined the study quality using the Q-Genie tool. Using the Mantel-Haenszel weighted means method, odds ratios were combined under both fixed- and random-effect models. Twenty-seven studies were included in the systematic review (five with IFITM3, two with Furin, three with TNF-α, and 17 with ACE1) and 22 in the meta-analysis (IFITM3 n = 3, TNF-α, and ACE1 n = 16). Meta-analysis indicated no association of 1) ACE1 rs4646994 and susceptibility, 2) ACE1 rs4646994 and asymptomatic COVID-19, 3) IFITM3 rs12252 and ICU hospitalization, and 4) TNF-α rs1800629 and death. On the other hand, significant results were found for ACE1 rs4646994 association with COVID-19 severity (11 studies, 692 severe cases, and 1,433 nonsevere controls). The ACE1 rs4646994 deletion allele showed increased odds for severe manifestation (OR: 1.45; 95% CI: 1.26-1.66). The homozygous deletion was a risk factor (OR: 1.49, 95% CI: 1.22-1.83), while homozygous insertion presented a protective effect (OR: 0.57, 95% CI: 0.45-0.74). Further reports are needed to verify this effect on populations with different ethnic backgrounds. Systematic Review Registration: https://www.crd.york.ac.uk/prosperodisplay_record.php?ID=CRD42021268578, identifier CRD42021268578.

Keywords: biomarkers; candidate genes; genetic association study; host genetics; polymorphism; transposable elements.

FIGURE 1

Study selection using Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines (16).

FIGURE 2

Forest plot illustrating ACE1 rs4646994 (Alu 287 pb) association with coronavirus disease 2019 (COVID-19) susceptibility. No significant results were observed. Case and control definitions are presented in Table 1. (A) C allele association. (B) C recessive model. (C) T recessive model.

FIGURE 3

Forest plot illustrating ACE1 rs4646994 (Alu 287 pb) association with symptom presence (asymptomatic × symptomatic). No significant allelic and genotypic effects were observed under the random model. Case and control definitions are presented in Table 2. (A) D-allele model. (B) D recessive model. (C) I recessive model.

FIGURE 4

Forest plot illustrating ACE1 rs4646994 (Alu 287 pb) association with COVID-19 severity (severe × others). Significant allelic and genotypic effects were observed. Case and control definitions are presented in Table 2. (A) D-allele model. D-allele was associated with increased risk of COVID-19 severity. (B) D recessive model. D/D genotype carriers showed increased odds to manifest severe COVID-19 compared with D/I and I/I carriers combined (C) I recessive model. I/I genotype carriers showed decreased odds to present severe COVID-19 compared with D/I and D/D carriers combined.

FIGURE 5

Forest plot illustrating IFITM3 rs12252 association with severity (non-ICU × ICU). No significant results were observed. Case and control definitions are presented in Table 3. (A) C allele association. (B) C recessive model. (C) T recessive model.

FIGURE 6

Forest plot illustrating TNF-α rs1800629 association with death (alive × dead). No significant results were observed under the random model. Case and control definitions are presented in Table 5. (A) C allele association. (B) C recessive model. (C) T recessive model.