Severity of coronavirus disease 19: Profile of inflammatory markers and ACE (rs4646994) and ACE2 (rs2285666) gene polymorphisms in Iraqi patients

Abstract

Susceptibility to coronavirus disease 2019 (COVID-19) and disease severity has recently been associated with inflammatory markers and genetic polymorphisms of ACE (angiotensin-converting enzyme) and ACE2 genes, but the evidence has been inconclusive. This case-control study (99 COVID-19 patients and 96 controls) sought to assess the significance of age, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and SARS-CoV-2 RT-PCR cycle threshold (Ct) in severity of COVID-19. Besides, two variants of ACE and ACE2 genes (rs4646994 and rs2285666, respectively) were analyzed to determine their role in COVID-19 susceptibility and/or disease severity. Results revealed that age, CRP and NLR were significantly elevated in severe cases compared to moderate cases, while RT-PCR Ct value was significantly decreased. Allele and genotypes of both variants were not associated with COVID-19 risk, with the exception of rs2285666 A allele. It showed a significantly higher frequency in female patients than in female controls (probability = 0.041 ) . In conclusion, the study indicated the role of age, CRP, NLR and SARS-CoV-2 RT-PCR Ct in susceptibility to COVID-19 severity. However, analysis of the ACE and ACE2 gene variants (rs4646994 and rs2285666, respectively) showed that the two variants were not associated with the risk of developing COVID-19.

The Role of ACE, ACE2, and AGTR2 Polymorphisms in COVID-19 Severity and the Presence of COVID-19-Related Retinopathy

“…Individuals with a D/D genotype were shown to have a higher incidence of pulmonary embolism and increased mortality rates, possibly due to increased levels of serum ACE [ 19 , 27 , 28 ]. This differs from our outcomes, otherwise consistent with other studies that found no association between the I/D polymorphism and disease severity [ 17 , 20 , 21 ]. One of the AGTR2 polymorphisms (rs1914711) was shown to increase the risk of severe COVID-19 in the Mayan population [ 29 ].…”

“…Thus, a protective role of A allele-related increase in ACE2 has been suggested, as it could help counterbalance the effects of increased Ag II resulting from RAAS dysregulation [ 20 ]. Nonetheless, in line with our results, several studies found no association with disease susceptibility or severity [ 17 , 21 , 22 ]. ACE insertion/deletion polymorphisms (rs4646994 and rs179752) have also been linked to COVID-19 severity.…”

“…Several factors could explain the lack of association between the selected polymorphisms and COVID-19 severity. First, the same polymorphisms were shown to affect diabetes, cardiovascular disease, and hypertension [ 17 , 18 , 19 , 20 , 21 , 22 ]. The studies did not exclude patients with said comorbidities, so their findings could reflect an association with diabetes and hypertension rather than COVID-19 [ 17 , 18 , 19 , 20 , 21 , 22 ].…”

“…One of its most studied single-nucleotide polymorphisms (SNP) is rs2285666 at the fourth base of the third intron (G > A). It has been suggested that its locus could alter alternative splicing of messenger RNA (mRNA) and affect ACE2 receptor gene expression [ 17 , 21 ]. Moreover, strong linkage disequilibrium with the other ACE2 receptor SNPs (rs1978124, rs714205) has been found [ 17 ].…”

“…In addition, it was shown to affect the retinal arteriole diameter [ 23 ]. It is important to note that ACE, ACE2, and AGTR2 polymorphisms have also been associated with hypertension, diabetes, coronary artery disease, and stroke [ 17 , 18 , 19 , 20 , 21 , 22 ]. As the previous studies did not exclude patients with comorbidities, it remains unclear whether the polymorphisms really play a role in COVID-19 severity or just reflect the higher prevalence of comorbidities in critically ill patients.…”