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. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-022-01670-3.

Innate Immune Gene Polymorphisms and COVID-19 Prognosis

“…After a broad literature review, we found only one additional study analyzing the contribution of rs1834481 in COVID-19 severity. Leal et al analyzed a larger cohort of Brazilian patients infected by SARS-CoV-2, but they did not observe any significant association of rs1834481 with COVID-19 severity; however, they used a different methodological approach comparing only patients with severe and mild disease, while they did not use, at least, the WHO classification as in our study [ 32 ].…”

Inflammasome-Related Genetic Polymorphisms as Severity Biomarkers of COVID-19

“…Therefore, we evaluated NLRP1 polymorphisms, and we did not find genetic distribution differences between patients with mild, moderate, severe, and critical COVID-19. In this sense, only one work has described a difference of rs12150220 NLRP1 between severe and mild Brazilian COVID-19 patients [26]. Additionally-and to the best of our knowledge-we assessed, for the first time, the potential relationship between NLRC4 polymorphisms and the severity of COVID-19 by observing the same results as the other inflammasomes.…”

“…It is important to mention that the previous results in the literature are controversial since other works have shown that some of the genetic variants that were studied in this work might modulate inflammasome activation, thus contributing to a worse or better prognosis in disease progression to severe outcomes. In particular, a relationship between COVID-19 aggravation and rs10754558 NLRP3 [21,30], rs6509365 CARD8 [21], rs2043211 CARD8 [26], rs16944 IL1B [31], and rs755622 MIF [32] have been described. It is reasonable to think that both the difference in ethnicity and criteria for stratifying patients according to disease severity between studies are contributing to this apparent discrepancy in the data.…”