PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

Abstract

Albeit the pathogenesis of COVID-19 remains unclear, host’s genetic polymorphisms in genes involved in infection and reinfection, inflammation, or immune stimulation could play a role in determining the course and outcome. We studied in the early phase of pandemic consecutive patients (N = 383) with SARS-CoV-2 infection, whose subsequent clinical course was classified as mild or severe, the latter being characterized by admission to intensive therapy unit or death. Five host gene polymorphisms (MERTK rs4374383, PNPLA3 rs738409, TLL-1 rs17047200, IFNL3 rs1297860, and INFL4 rs368234815) were assessed by using whole nucleic acids extracted from nasopharyngeal swabs. Specific protease cleavage sites of TLL-1 on the SARS-CoV-2 Spike protein were predicted in silico. Male subjects and older patients were significantly at higher risk for a severe outcome (p = 0.02 and p < 0.001, respectively). By considering patients ≤65 years, after adjusting for potential confounding due to sex, an increased risk of severe outcome was found in subjects with the GG genotype of PNPLA3 (adj-OR: 4.69; 95% CI = 1.01–22.04) or TT genotype of TLL-1 (adj-OR=9.1; 95% CI = 1.45–57.3). In silico evaluation showed that TLL-1 is potentially involved in the Spike protein cleavage which is essential for viral binding and entry into the host cells using the host receptor angiotensin-converting enzyme 2 (ACE2). Subjects carrying a GG genotype in PNPLA3 gene might have a constitutive upregulation of the NLRP3 inflammasome and be more prone to tissue damage when infected by SARS-CoV-2. The TT genotype in TLL-1 gene might affect its protease activity on the SARS-CoV-2 Spike protein, enhancing the ability to infect or re-infect host’s cells. The untoward effect of these variants on disease course is evident in younger patients due to the relative absence of comorbidities as determinants of prognosis. In the unresolved pathogenetic scenery of COVID-19, the identification of genetic variants associates with more prolonged course or with a severe outcome of infection would support the development of predictive tools useful to stratify subjects by risk class at presentation. Moreover, the individuation of key genes could contribute to a better understanding of the pathways involved in the pathogenesis, giving the basis for rational therapeutic approaches.

Effectiveness of mRNA COVID-19 Vaccination on SARS-CoV-2 Infection and COVID-19 in Sicily over an Eight-Month Period

“…However, we suppose that vaccination coverage was increased among the at-higher risk of COVID-19 complications, including those with comorbidities, and thus the vaccine effectiveness observed in this study could underestimate the real protection effect. Moreover, as a second limitation, our considerations are set on the assumption that cellular immunity has no role and that new strains with comparable or greater risk are introduced regularly [ 21 , 22 ]. Unfortunately, this latter information about SARS-CoV-2 variants was not available to us and we cannot exclude vaccine effectiveness could change between different viral strains.…”

Potential Genes Associated with COVID-19 and Comorbidity

“…The IFNL4 variant rs12979860 is associated with the presence of COVID-19 in the Spanish population, independent of gender, age, and disease severity, which may be related to reduced virus clearance 26 . The status of the PNPLA3 variant rs738409 and the TLL-1 variant rs17047200 is related to SARS-COV-2-induced infection 27 . The frequencies of TMPRSS2 variants rs12329760 and rs2298659 are associated with the severity of COVID-19, especially in young men and older women.…”

SARS-Cov2 acute and post-active infection in the context of autoimmune and chronic inflammatory diseases

“…The NLRP3 inflammasome is overactivated in multiple autoinflammatory disorders including SLE and RA [ 51 ]. In addition, NLRP3 inflammasome related polymorphisms are associated with susceptibility, disease severity and/or therapeutic responses in SAD [ 52 ], and they are suspected of contributing to disease severity in COVID-19 [ 53 ].…”