ACE and ACE2 Gene Variants Are Associated With Severe Outcomes of COVID-19 in Men

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, affecting more than 219 countries and causing the death of more than 5 million people worldwide. The genetic background represents a factor that predisposes the way the host responds to SARS-CoV-2 infection. In this sense, genetic variants of ACE and ACE2 could explain the observed interindividual variability to COVID-19 outcomes. In order to improve the understanding of how genetic variants of ACE and ACE2 are involved in the severity of COVID-19, we included a total of 481 individuals who showed clinical manifestations of COVID-19 and were diagnosed by reverse transcription PCR (RT-PCR). Genomic DNA was extracted from peripheral blood and saliva samples. ACE insertion/deletion polymorphism was evaluated by the high-resolution melting method; ACE single-nucleotide polymorphism (SNP) (rs4344) and ACE2 SNPs (rs2285666 and rs2074192) were genotyped using TaqMan probes. We assessed the association of ACE and ACE2 polymorphisms with disease severity using logistic regression analysis adjusted by age, sex, hypertension, type 2 diabetes, and obesity. The severity of the illness in our study population was divided as 31% mild, 26% severe, and 43% critical illness; additionally, 18% of individuals died, of whom 54% were male. Our results showed in the codominant model a contribution of ACE2 gene rs2285666 T/T genotype to critical outcome [odds ratio (OR) = 1.83; 95%CI = 1.01–3.29; p = 0.04] and to require oxygen supplementation (OR = 1.76; 95%CI = 1.01–3.04; p = 0.04), in addition to a strong association of the T allele of this variant to develop critical illness in male individuals (OR = 1.81; 95%CI = 1.10–2.98; p = 0.02). We suggest that the T allele of rs2285666 represents a risk factor for severe and critical outcomes of COVID-19, especially for men, regardless of age, hypertension, obesity, and type 2 diabetes.

Global distribution of ACE1 (rs4646994) and ACE2 (rs2285666) polymorphisms associated with COVID-19: A systematic review and meta-analysis

“…According to the defined criteria, titles, abstracts, and full-text of articles were reviewed by two separate authors. In this meta-analysis, characteristics such as first author, publication year, country, allelic/genotype distribution of rs4646994, and allelic/genotype distribution of rs2285666 were considered as eligible criteria ( Table 1 ) [ [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] ].…”

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

“…On the other hand, other studies have observed different results. Martínez-Gómez et al have recently identified that the T allele of ACE2 rs2285666 was associated with higher risk for critical outcomes (OR 1.89, 95% CI 1.06–3.35) of COVID-19, especially for men [ 9 ]. Wulandari et al observed that the TMPRSS2 rs12329760 was associated with a higher viral load but not with a more severe acute condition [ 10 ].…”

Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population

“…Next, we performed a replication analysis of the 12 variants reported to be associated with COVID-19 severity in previous studies. We have chosen associations that emerged in large GWAS meta-studies ( Horowitz et al, 2022 ; Roberts et al, 2022 ) and recent studies that analyzed associations of ACE2 genetic variants with COVID-19 severity ( Martínez-Gómez et al, 2022 ; Sabater Molina et al, 2022 ) ( Supplementary Table S6 ). Our selection approach was focused on variants that showed association with severity and not with susceptibility to COVID-19.…”