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

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.

Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis?

ITGAM-ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM-ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis.

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.