Genetic factors associated with increased severity of Covid‐19
-
Zahra Shishegar,1,*
1. Department of Genetics, Faculty of Biological Sciences and Technology, Shahid Ashrafi Esfahani University, Isfahan, Iran
- Introduction: Covid19 is the third most aggressive coronavirus that spreads rapidly and kills many people. It is a multigenic and multifactorial disease with many genetic and environmental determinants. The present review gives a brief overview of different genes involved in the infection by SARS-CoV-2 and its association with disease severity.
- Methods: searching review studies including this field in web browser
- Results: Several studies indicated that the genetic variants of the SARS‐CoV‐2 entry mechanism‐related (angiotensin‐converting enzymes, transmembrane serine protease‐2, furin) and host innate immune response‐related genes (interferons [IFNs], interleukins, toll‐like receptors), and human leukocyte antigen, ABO, 3p21.31, and 9q34.2 loci are significantly related to Covid‐19 severity.
1-ANGIOTENSIN‐CONVERTING ENZYMES
Angiotensin I‐converting enzyme (ACE) and angiotensin‐converting enzyme‐2 (ACE2) are homolog genes that regulate physiological homeostasis of renin–angiotensin system (RAS). SARS‐CoV‐2 uses the ACE2 receptors to invade the target cells. Transcriptome analyses of 700 lung samples revealed that ACE2 was highly expressed in severe patients, compared with controls, and comorbidities may lead to higher chances of developing severe Covid‐19. On the contrary, some reports have indicated a negative correlation between ACE2 expression and Covid‐19 severity.
2- GENETIC VARIANTS OF CELLULAR PROTEASES
Transmembrane serine protease‐2: TMPRSS2 gene encodes a serine protease enzyme that is involved in cleavage and activation of the SARS‐CoV‐2 spike protein during membrane fusion. it was suggested that genotyping studies of Covid‐19 patients could aid in understanding the impact of TMPRSS2 variations on clinical outcomes.
Furin: SARS‐CoV‐2 spike protein contains a multibasic S1/S2 site where host cell protease Furin can cleave S protein Furin is essential for proteolytic activation of SARS‐CoV‐2, so inhibition of this protease ensures a therapeutic approach for treatment of Covid‐19.
3- GENETIC VARIATIONS OF IMMUNITY COMPONENTS
Interferons: for example IFNAR1 and IFNAR2 are a family of specialized cytokines that activate a cell signaling cascade, controlling the induction of hundreds of interferon‐ stimulated genes. Three distinct types of IFNs, Types I, II, and III, mediate antiviral response and activate host defence against viral infections.
Interleukins (ILs): IL‐1 signaling pathway component TMEM189–UBE2V1 was the most significant gene locus associated with severity. IL6 is a pro-inflammatory cytokine The overexpression of this cytokine was associated with increased COVID-19 risk and death.
Toll‐like receptors (TLRs): TLRs are a family of innate immune receptor molecules known as pattern recognition receptors (PRRs). TLR3 is the most widely expressed TLR that recognizes virus‐ derived double‐stranded (ds) sRNA.
4- HLA LOCUS
The HLA region consists of more than 240 genes and they are divided into three classes, namely I, II, and III. The HLA system consists of a group of proteins that play a crucial role in the antigen presentation and genetic diversity. HLA is the most polymorphic genetic locus in human. The frequencies of the HLA‐C*07:29 and B*15:27 alleles were significantly higher in Covid‐19 patients.
5- 3P21.31 AND 9Q34.2 LOCI
Genome wide association study( GWAS) of severe Covid‐19 with respiratory failure revealed a significant association with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2. CXCL16 and CXCR6 SLC6A20 are genes are within the 3p21.31 locus. Two GWAS of severe Covid‐19 reported that blood group A shows higher risk than other blood groups, whereas O group displays a protective effect as compared with other blood groups.
6- APOLIPOPROTEINS
Apolipoprotein E (APOE) is a polymorphic gene locus and ε2/ε3/ε4 alleles code for three major isoforms in plasma.It was found that individuals homozygous for APOE4 were more likely to be positive for Covid‐19, and thus severe disease.
7- OTHER GENES
DPP9 locus was also associated with severe Covid‐19 in a GWAS and the COVID‐19 HGI report. Researches identified four missense and one intronic noncoding variant in four genes ERAP2 (rs150892504), BRF2 (rs138763430), TMEM181 (rs117665206), and ALOXE3 (rs147149459 and rs151256885) that significantly increase risk of death in Covid‐19 patients.
- Conclusion: Identifying genetic markers associated with the susceptibility or clinical outcome of COVID-19 could provide an essential contribution to the knowledge of this disease for the detection of susceptible individuals or populations and the design of therapeutic strategies (i.e., vaccine and pharmacologic treatment).
- Keywords: COVID-19, Genetic variants, SARS-CoV-2, Polymorphism, Severity and mortality
