Dataset Information

A common variant close to the "tripwire" linker region of NLRP1 contributes to severe COVID-19.

ABSTRACT:

Objective and design

The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease.

Methods

To address this question, we performed an association study of NLRP1, DPP9, CARD8, IL1B, and IL18 single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients.

Results

The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases.

Conclusion

Inflammasome genetic background contributes to individual response to SARS-CoV-2.

SUBMITTER: Leal VNC

PROVIDER: S-EPMC9684769 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

A common variant close to the "tripwire" linker region of NLRP1 contributes to severe COVID-19.

Leal Vinicius N C VNC Paulino Leandro M LM Cambui Raylane A G RAG Zupelli Thiago G TG Yamada Suemy M SM Oliveira Leonardo A T LAT Dutra Valéria de F VF Bub Carolina B CB Sakashita Araci M AM Yokoyama Ana Paula H APH Kutner José M JM Vieira Camila A CA Santiago Wellyngton M de S WMS Andrade Milena M S MMS Teixeira Franciane M E FME Alberca Ricardo W RW Gozzi-Silva Sarah C SC Yendo Tatiana M TM Netto Lucas C LC Duarte Alberto J S AJS Sato Maria N MN Venturini James J Pontillo Alessandra A

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 20221123 10-11

<h4>Objective and design</h4>The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease.<h4>Methods</h4>To address this question, we performed an association study of NLRP1, DPP9, CARD8, ...[more]

PMID: 36416944

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Project description:BackgroundThe human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.MethodsWe focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry.ResultsWe show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10-3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells.ConclusionTMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

Dataset Information

A common variant close to the "tripwire" linker region of NLRP1 contributes to severe COVID-19.

Objective and design

Methods

Results

Conclusion

Publications

A common variant close to the "tripwire" linker region of NLRP1 contributes to severe COVID-19.

Similar Datasets

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