The findings of this comprehensive study demonstrate considerable evidence that there are associations between two polymorphisms of the CRP gene (rs1205 and rs1800947) with COVID-19 mortality.

CRP levels were statistically significantly higher in deceased patients than in recovered patients, as shown in this study. Several studies have found that CRP can be used as a biomarker for COVID-19 infection severity and mortality8,19. Angiotensin II converting enzyme (ACE2) can produce CRP when it interacts with SARSCoV220. The production of CRP by hepatocytes is stimulated by cytokines like interleukin6 (IL-6) and tumor necrosis factor- (TNF-) during COVID-19 development21. In one sense, CRP is responsible for activating the complement system, which contributes to inflammation. In contrast, severe COVID-19 patients will significantly damage their alveolar epithelial and endothelial barriers. The alveolar macrophages and epithelial cells are capable of producing a variety of cytokines and chemokines during an infection with SARS-CoV-2. In this phase, adaptive immunity is challenged by the significant decreases in lymphocytes and the T-cell-mediated immunosuppression. Therefore, in the context of COVID-19, uncontrolled SARS-CoV-2 infection could result in considerable macrophage infiltration, exacerbating acute lung damage22,23.

A number of SNPs are associated with plasma levels of CRP on the CRP gene. In addition to rs1205 and rs1800947 in the 3- and 5-flanking regions, rs1417938 is present in the intron, and rs1800947 appears in exon 224,25.

Currently, this is the first study to evaluate the relationship between CRP rs1205 and rs1800947 and COVID-19 mortality. COVID-19 death rates were significantly higher in patients with the CRP rs1205 T allele. In all patients, the MAF (T allele) was 0.42, which was lower in recovered patients (0.30) than in died patients (0.55). In other regions, the T allele was found in 0.597 Asians, 0.609 East Asians, 0.342 South Asians, 0.545 other Asians, 0.332 Europeans, 0.333 Latin Americans, and 0.201 Africans, as reported in the NCBI dbSNP database (https://www.ncbi.nlm.nih.gov/snp/rs1205).

Several studies have demonstrated that CRP levels are functionally influenced by the rs1205 SNP. CRP is a major component of the innate immune system, so this SNP may have an impact on SARS-Co-2 pathogenesis. A genome-wide association meta-analysis found that an intron variant (rs67579710) was associated with COVID-19 hospitalizations in 24,741 cases and 2,835,201 controls. Due to its location within the thrombospondin-3 gene, this variant may affect thrombosis related to COVID-19 rather than inflammatory pathways26,27.

According to the current study, all three variants of CRP rs1205 T allele were correlated with COVID-19 mortality. Several studies have found that CRP rs1205 affects both clinical outcomes and vaccination outcomes. It has been suggested that the frequency of rs1205 T allele was significantly higher in patients with community-acquired pneumonia compared with healthy controls, and T allele was associated with an increased risk of infection. Furthermore, the rs1205 CT and TT genotypes were substantially more common in patients with severe community-acquired pneumonia than those with non-severe community-acquired pneumonia18.

As shown in our study, numerous studies with different diseases have shown that the rs1205 T allele is associated with lower serum CRP levels18,28. Since the rs1205 TT genotype results in lower serum CRP levels and is associated with lymph node metastasis in this form of cancer, rs1205 may be associated with thoracic esophageal squamous cell cancer, myocardial infarction, systemic lupus erythematosus and lupus nephritis29,30. In studies with higher baseline CRP levels, pre-eclampsia risk is positively correlated with CRP genotypes. In contrast, as in the current study, CRP genotypes (including the rs1205 T allele) associated with lower CRP levels and have been correlated with greater infectious load. There may have been balanced selection on CRP polymorphisms during evolution because of these disparate effects18,31,32.

In this study, patients with the CRP rs1800947 G allele had a significantly higher death rate from COVID-19. In all patients, the MAF (G allele) was 0.47, with recovery patients having a lower value (0.40) than dying patients having a higher value (0.54). A study in Iran found that the frequency of G-allele was 0.45, which is similar to what we found in our study33. According to NCBI dbSNP database (https://www.ncbi.nlm.nih.gov/snp/rs1800947), Asians and East Asians were most likely to have the G allele 0.036, South Asians 0.000, other Asians 0.040, Europeans 0.056, Latin Americans 0.024, and Africans 0.010, respectively.

According to our results, the COVID-19 mortality rate was correlated with CRP rs1800947 GG genotype in all three variants, as well as with CRP rs1800947 CG genotype in the Alpha and Delta variants of the gene.

There is a strong association between the CRP rs1800947 and CRP expression and it has been shown to be associated with heart disease, diabetes, and cancer33,34,35. In contrast to the results of this study, previous reports have demonstrated that C-allele carriers have lower plasma levels of CRP than GG genotype. Clinical diagnosis and severity assessment of community-acquired pneumonia and COVID-19 are based on serum CRP levels19,36,37. The high mortality rate in deceased people infected with COVID-19 with GG genotype could be due to their higher serum CRP levels.

There is no correlation between the majority of SNPs and diseases or functional issues. In contrast, if SNPs are located on genes or regulatory regions such as promoters, enhancers, they may influence the function of genes involved in disease mechanisms36. CRP rs1800947 may have different effects. Since the rs1800947 SNP is silent, the mechanism behind expressed CRP levels could be linkage disequilibrium between the rs1800947 polymorphism and other functional SNPs both inside and outside the CRP gene. There is also the possibility that this polymorphism alters the kinetics of CRP translation, causing variable levels of CRP throughout the body38.

In this study, several limitations were observed that should be considered in future studies. Because there were no healthy controls in this study, the outcomes were not compared with healthy controls. This study should be confirmed with more research on other ethnic groups in Iran, since this country has a variety of ethnicities.

In conclusion, this study showed that COVID-19 mortality rate was correlated with CRP rs1205 TT genotypes and CRP rs1800947 GG genotypes across all three variants. In addition, higher CRP levels were observed in individuals with the CRP rs1205 CC genotype and the CRP rs1800947 GG genotype. To verify these findings, further research should be conducted in other regions.

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The death rate of COVID-19 infection in different SARS-CoV-2 variants was related to C-reactive protein gene ... - Nature.com