The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: a systematic review and meta-analysis

Abstract

Genes involved in the regulation of viral recognition and its entry into a host cell have been identified as candidates for genetic association studies on COVID-19 severity. Published findings on the effects of polymorphisms within ACE1 , ACE2 , TMPRSS2 , IFITM3 and VDR genes remained inconclusive, so we conducted a systematic review and meta-analysis in order to elucidate their potential involvement in the genetic basis underlying the severity of COVID-19 and/or an outcome of SARS-CoV-2 infection. Identification of potentially eligible studies was based on PubMed, Scopus and Web of Science database search. Relevant studies (n=29) with a total number of 8247 SARS-CoV-2-positive participants were included in qualitative synthesis, while results of 21 studies involving 5939 were pooled in meta-analysis. Minor allele I of rs1799752 located within ACE1 was identified as a protective variant against severe COVID-19, while its effect on mortality rate was opposite. Similarly, minor allele A of ACE2 polymorphism, rs2285666, was found to associate with a decreased risk of severe COVID-19 ( P = 0.003, OR = 0.512, 95 % CI = 0.331-0.793). Statistical significance was also seen for the association between COVID-19 severity and rs12329760 located within TMPRSS2 . Our results did not support the supposed association of rs12252 in IFITM3 and polymorphisms within VDR with disease severity. We conclude that genetic variants within ACE1 , ACE2 and TMPRSS2 may be potential biomarkers of COVID-19 severity, which needs to be further confirmed in a larger set of studies.

Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors

“…The genotype distributions deviated from that expected based on the Hardy–Weinberg equilibrium ( p < 0.01) which has been also extensively found in previous studies [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Overall, no significant differences in long-COVID symptoms were observed depending on the genotypes of any SNP: ACE2 rs2285666 ( Table 2 ), ACE2 rs2074192 ( Table 3 ), TMPRSS2 rs12329760 ( Table 4 ), TMPRSS2 rs2070788 ( Table 5 ).…”

“…Some studies have correlated the T (A) allele of the ACE2 rs2285666 [ 4 ] and of TMPRSS2 rs12329760 [ 5 ] SNPs with lower severity of COVID-19 in an Indian population. These data have been also replicated in a multicountry study [ 6 ] and confirmed by the meta-analysis by Dobrijevic et al concluding that T alleles of ACE2 rs2285666 (OR 0.512, 95% CI 0.331–0.793) and TMPRSS2 rs12329760 (OR 0.734, 95% CI 0.560–0.960) SNPs were associated with lower risk of developing severe COVID-19 [ 7 ]. Another meta-analysis has found that TMPRSS2 rs12329760 was not associated with more severe COVID-19 manifestations, whereas ACE2 rs2285666 and ACE2 rs2074192 SNPs were associated with more severe COVID-19 manifestations by genotype but not by allele [ 8 ].…”

“…Previous studies have investigated the associations of SNPs and the predisposition to and the severity of COVID-19 disease to identify individual risk factors [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. It seems clear that ACE2 and TMPRSS2 receptors are important for the invasion of the SARS-CoV-2 virus into the host cell and the aggressiveness of the infection [ 30 ].…”

“…It seems clear that ACE2 and TMPRSS2 receptors are important for the invasion of the SARS-CoV-2 virus into the host cell and the aggressiveness of the infection [ 30 ]. However, the role of these SNPs in the acute phase of the infection are still inconclusive with results from single studies showing an association with the severity of the infection, whereas meta-analysis have not confirmed such association [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

“…Most studies investigating the role of these ACE2 or TMPRSS2 SNPs have focused on the risk of being infected or the severity of COVID-19 disease in the acute phase [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. No study has investigated the potential association between polymorphisms of ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) genes and the presence of long-term post-COVID symptoms.…”