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.
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 (
,
,
,
,
,
,
,
,
, and
) 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
,
,
,
,
,
, and
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.
Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether ...E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD
. We recruited patients with rheumatoid arthritis (RA)-ILD
(
= 21) and systemic sclerosis (SSc)-ILD
(
= 21). We included comparison groups of patients: RA-ILD
(
= 25), SSc-ILD
(
= 20), and idiopathic pulmonary fibrosis (IPF) (
= 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD
and IPF patients in comparison to RA-ILD
patients. Additionally, SSc-ILD
and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD
. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD
from RA-ILD
patients, and ICAM-1 to distinguish SSc-ILD
from SSc-ILD
patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD
and SSc-ILD
patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD
patients as well as of ICAM-1 in SSc-ILD
patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD
and SSc-ILD
patients, respectively.
Objective
To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA).
Methods
We performed a genome‐wide association ...study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima‐media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals.
Results
A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome‐wide level of significance (minor allele G β coefficient 0.142, P = 1.86 × 10−8). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein–protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate–adjusted P = 4.01 × 10−3). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 × 10−4, P = 5.94 × 10−4, and P = 2.46 × 10−4, respectively).
Conclusion
The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.
Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory ...conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median interquartile range) were significantly higher in ILD patients than in controls (1.05 0.75-1.51 ng/mL versus 0.81 0.65-0.98 ng/mL in healthy controls;
< 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 0.80-1.72 ng/mL versus 0.99 0.66-1.32 ng/mL;
= 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of
polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.
Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC ...frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD+ patients and subjects from comparative groups (20 SSc-ILD− and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34+, CD45low, CD309+, and CD133+. A significant increase in EPC frequency was found in SSc-ILD+ patients when compared to HC (p < 0.001). SSc-ILD+ patients exhibited a higher EPC frequency than SSc-ILD− patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p < 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD+ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC frequency may be considered as a biomarker of ILD in SSc patients.
Patients with clinically evident coronary artery disease differ in their rate of progression, which impacts prognosis. We aimed to characterize serum and genetic markers in patients with rapid ...clinical progression (RCP) of coronary artery disease vs those with long standing stable (LSS) disease.
Retrospective study of cases (RCP) and controls (LSS) (1:2). Patients requiring ≥ 2 revascularizations due to atherosclerotic progression in the 10 years after a first angioplasty were considered to be RCP and those without events during the same period after the first angioplasty were considered to have LSS disease. After patient selection, we analyzed serum values, mRNA expression and genetic polymorphisms of inflammatory markers, including interleukin-6, C-reactive protein, and tumor necrosis factor (TNF)-a, and atherogenic markers consisted of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, sterol regulatory element binding transcription factor 2, and apolipoprotein-B.
The study included 180 patients (58 RCP and 122 LSS). Demographic characteristics, classic risk factors and the extent of coronary disease were similar in the 2 groups. Patients with RCP showed higher serum levels of interleukin-6 and PCSK9 and higher TNF mRNA expression. Interleukin-6 rs180075C, TNF rs3093664 non-G and PCSK9 rs2483205 T alleles conferred a risk of RCP (P<.05 in all cases). Among patients with RCP, 51.7% had all 3 risk alleles vs 18% of those with LSS (P<.001).
We suggest the existence of specific phenotypic and genotypic markers associated with RCP of coronary artery disease that could help to individualize the type and intensity of treatment.
La progresión de la enfermedad coronaria una vez se hace evidente a la clínica tiene una gran variabilidad interindividual. El objetivo es determinar marcadores séricos y genéticos en pacientes con rápida progresión clínica (RPC) de la enfermedad coronaria frente a pacientes con estabilidad clínica mantenida (ECM).
Estudio retrospectivo de casos (RPC) y controles (ECM) (1:2). Se consideró RPC a los pacientes que precisaron al menos 2 revascularizaciones por progresión de la ateroesclerosis en los 10 años posteriores a una primera angioplastia y ECM a aquellos sin eventos durante el mismo periodo tras la primera angioplastia. Una vez seleccionados, se determinaron los valores séricos, la expresión de ácido ribonucleico mensajero (ARNm) y polimorfismos genéticos de interleucina 6, proteína C reactiva y factor de necrosis tumoral alfa (TNFα) como marcadores de inflamación y proproteína convertasa subtilisina/kexina tipo 9 (PCSK9), receptor de lipoproteínas de baja densidad, proteína 2 de unión a elementos reguladores de esteroles y apolipoproteína B como marcadores aterogénicos.
Se incluyó a 180 pacientes (58 en RPC y 122 en ECM). Las características basales demográficas, del perfil de riesgo clásico y de la extensión de la enfermedad coronaria fueron comparables. El grupo de RPC presentó valores séricos más altos de interleucina 6 y PCSK9 y mayor expresión de ARNm de TNF. Los alelos de Interleucina-6 rs180075C, de TNF rs3093664 non-G y de PCSK9 rs2483205 T confieren riesgo de RPC (p<0,05 en todos los casos). Un 51,7% de los pacientes del grupo RPC presentaron los tres alelos de riesgo frente al 18% de los pacientes del grupo en ECM (p<0,001).
Se propone la existencia de marcadores genotípicos y fenotípicos asociados con la RPC de enfermedad coronaria y que podrían servir para individualizar la intensidad y el tipo de tratamiento.
Cardiovascular (CV) disease is the main cause of mortality in axial spondyloarthritis (axSpA). CV risk is enhanced by dysregulation of adipokines. Low omentin levels were associated with metabolic ...dysfunction and CV disease in conditions different from axSpA. Accordingly, we evaluated the genetic and functional implication of omentin in CV risk and subclinical atherosclerosis in a cohort of 385 axSpA patients. Subclinical atherosclerosis was evaluated by carotid ultrasound. Omentin rs12409609, in linkage disequilibrium with a polymorphism associated with CV risk, was genotyped in 385 patients and 84 controls. Serum omentin levels were also determined. omentin mRNA expression was assessed in a subgroup of individuals. Serum and mRNA omentin levels were lower in axSpA compared to controls. Low serum omentin levels were related to male sex, obesity, inflammatory bowel disease (IBD) and high atherogenic index. rs12409609 minor allele was associated with low omentin mRNA expression in axSpA. No association was observed with subclinical atherosclerosis at the genetic or functional level. In conclusion, in our study low omentin serum levels were associated with CV risk factors in axSpA. Furthermore, rs12409609 minor allele may be downregulating the expression of omentin. These data support a role of omentin as a CV risk biomarker in axSpA.
Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not ...been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.
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.
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