Association of polymorphisms in tumor necrosis factors with SARS‐CoV‐2 infection and mortality rate: A case‐control study and in silico analyses

Abstract

The present coronavirus disease 2019 is spreading rapidly and existing data has suggested a number of susceptibility factors for developing a severe course of the disease. The current case-control experiment is aimed to study the associations of genetic polymorphisms in tumor necrosis factors (TNFs) with COVID-19 and its mortality rate. A total of 550 participants (275 subjects and 275 controls) were enrolled. The tetra-amplification refractory mutation system polymerase chain reaction technique was recruited to detect −308G>A TNFα and +252A>G TNFβ polymorphisms among the Iranian subjects. We demonstrated that carriers of the G allele of TNFβ-252A/G, rs909253 A>G were more frequent in COVID-19 subjects compared to the healthy group and this allele statistically increased the disease risk (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.23-1.96, p < 0.0001). At the same time, the A allele of TNFα-311A/G, rs1800629 G>A moderately decreased the risk of COVID-19 (OR = 0.68, 95% CI = 0.53-0.86, p < 0.002). Also, we analyzed the various genotypes regarding the para-clinical and disorder severity; we found that in the AA genotype of TNFβ-252A/G (rs909253 A>G), the computed tomography scan pattern was different in comparison to cases carrying the AG genotype with p 1 < 0.001. In addition, in the severe cases of COVID-19, leukocyte and neutrophil count and duration of intensive care unit hospitalization in the deceased patients were significantly increased (p < 0.001). Moreover, the TNFα-311A/G (rs1800629 G>A) variant is likely to change the pattern of splicing factor sites. Our findings provided deep insights into the relationship between TNFα/TNFβ polymorphisms and severe acute respiratory syndrome coronavirus 2. Replicated studies may give scientific evidence for exploring molecular mechanisms of COVID-19 in other ethnicities.

Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity

“…The genotype distribution and allele frequency of the studies on susceptibility and severity are summarized in Table 2 and Table 3 , respectively. The studies for susceptibility analysis included: ACE1 I/D rs4646994/rs1799752 ( Annunziata et al, 2021 Aug 20 , Gong et al, 2021 , Aladag et al, 2021 Sep , Papadopoulou et al, 2022 Mar , Akbari et al, 2022 Feb , Calabrese et al, 2021 Jan , Saad et al, 2021 Dec , Möhlendick et al, 2021 Oct 1 , Gómez et al, 2020 Dec , Hubacek et al, 2021 Aug , Kouhpayeh et al, 2021 Nov 17 , Mahmood et al, 2022 Feb , Mir et al, 2021 Oct 27 ); ACE2 rs2285666 ( Möhlendick et al, 2021 Oct 1 , Alimoradi et al, 2022 Mar 19 , Gómez et al, 2020 Dec , Mahmood et al, 2022 Feb ); APOE rs429358 ( Kuo et al, 2020 May 26 , Al-Jaf et al, 2021 Nov , Hilser et al, 2021 Jan ); CCR5 rs333 ( Cuesta-Llavona et al, 2021 Sep , Bernas et al, 2021 Apr , Gómez et al, 2020 ); IFITM3 rs12252 ( Abbas et al, 2021 Jun 12 , Schönfelder et al, 2021 Jun , Gómez et al, 2021 Jan ); TMPRSS2 rs12329760 ( Taha et al, 2022 Mar 1 , Andolfo et al, 2021 , Schönfelder et al, 2021 Apr , Wulandari et al, 2021 ), and TNFA rs1800629 ( Rokni et al, 2022 Apr , Saleh et al, 2020 Nov , Heidari Nia et al, 2022 ). Severity-wise analysis was performed for ACE1 I/D rs4646994/rs1799752 ( Karakaş Çelik et al, 2021 Oct , Gong et al, 2021 , Gunal et al, 2021 Jun , Martínez-Gómez et al, 2022 Feb , Baştuğ et al, 2021 Dec 8 , Akbari et al, 2022 Feb , Saad et al, 2021 Dec , Möhlendick et al, 2021 Oct 1 , Cafiero et al, 2021 May , Gómez et al, 2020 Dec , Hubacek et...…”

Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients

“…The present experiment is an in-hospital prospective study conducted at Zahedan University of Medical Sciences, Zahedan, Iran. According to a previously published protocol, patients with SARS-CoV-2 infection were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) (Heidari Nia et al 2021 ; Lee et al 2008 ). A total of 67 confirmed COVID-19 patients with a mild or moderate scenario, who had been referred from October 2020 to September 2021, were enrolled in this study.…”

“…An infection of the respiratory tract, coronavirus disease 2019 (COVID-19), is caused by the newly identified severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) (Ghaznavi et al 2022 ; Heidari Nia et al 2021 ; Sivasankarapillai et al 2020 ), imposing an average mortality rate of 14% to the communities worldwide (Ghaznavi et al 2022 ). Recognized widely as a systemic hyper-inflammatory condition in severe cases, COVID-19 is associated with excess production of several cytokines and chemokines, several of which are directly modulated by the SARS-CoV-2 virus itself (Liu et al 2007 ; Yan et al 2006 ).…”

Viral and Host Genetic and Epigenetic Biomarkers Related to SARS-CoV-2 Cell Entry, Infection Rate, and Disease Severity

“…Several additional polymorphisms were associated with COVID-19: PCDH15 [ 48 , 53 ], ABO [ 48 , 56 , 57 , 58 ], APOE [ 59 ], RIMBP3 [ 47 , 48 ], GOLGA8B [ 47 , 48 ], C3 [ 60 , 61 ], CCR5 [ 62 ], IL37 [ 63 ], IFNAR2 [ 31 ], DPP9 [ 31 ], IFNL4 [ 64 ] TNFRSF13B [ 39 , 40 ], TNF [ 39 , 68 ], TNFRSF1A [ 39 ], TBK1 [ 39 ], IFITM3 [ 42 , 43 ], ACE [ 44 , 45 , 46 ], IRF7 [ 48 , 52 ], TMPRSS2 [ 36 , 37 , 38 ], HLA [ 48 , 49 , 50 , 51 ], and AGT [ 46 ] ( Table 1 ).…”