HLA-B*08 identified as the most associated MHC locus for anti-carbamylated protein antibody-positive/anti-CCP-negative rheumatoid arthritis

Objective: Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. Methods: Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP-), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 × 10-5 . Results: The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 × 10-7 ; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion: These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies. © 2020, American College of Rheumatology

Influence of coronary artery disease and subclinical atherosclerosis related polymorphisms on the risk of atherosclerosis in rheumatoid arthritis

A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2). In the present study, we assessed the potential association of these polymorphisms with CVD in Southern European RA patients. We also assessed if polymorphisms implicated in the increased risk of subclinical atherosclerosis in non-rheumatic Caucasians (ZHX2, PINX1, SLC17A4, LRIG1 and LDLR) may influence the risk for CVD in RA. 2,609 Spanish patients were genotyped by TaqMan assays. Subclinical atherosclerosis was determined in 1,258 of them by carotid ultrasonography (assessment of carotid intima media thickness and presence/absence of carotid plaques). No statistically significant differences were found when each polymorphism was assessed according to the presence/absence of cardiovascular events and subclinical atherosclerosis, after adjustment for potential confounder factors. Our results do not show an association between these 15 polymorphisms and atherosclerosis in RA

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA

Valoración de riesgo cardiovascular mediante técnicas no invasivas en pacientes con artritis reumatoide

El estudio de la velocidad de la onda de pulso (VOP) y el índice de aumento (AIx) como marcadores de rigidez arterial está escasamente valorado en la artritis reumatoide (AR). Esta tesis se plantea evaluar la validez de estas técnicas para estimar el riesgo cardiovascular en pacientes con AR. Adicionalmente, se pretende determinar la asociación de la VOP y el AIx con factores de riesgo cardiovascular clásicos, parámetros inflamatorios, y los de daño vascular determinados por ecografía carotidea. No se ha hallado asociación entre el AIx con los parámetros estudiados; tampoco se ha identificado asociación de la VOP con la tensión arterial sistólica ni los hallazgos patológicos en ecografía carotidea. En menores de 55 años, la VOP se relaciona con el grosor de íntima media y los eventos cardiovasculares. Estos hallazgos apoyan el uso de la VOP como herramienta útil para la estratificación del riesgo cardiovascular de pacientes con AR

Descriptive study of a cohort of COVID-19 hospitalized patients in Spain

Background: Several descriptive cohort studies of patients affected by COVID-19 have been published. Objective: To describe the characteristics of patients with SARS-CoV-2 infection who were admitted to Hospital Universitario la Plana, Castellón, Spain. Methods: Retrospective, observational cohort study that included 18-year-old or older patients who were consecutively admitted with SARS-CoV2 confirmed infection. Demographic characteristics, comorbidities, clinical symptoms, laboratory results and radiological tests are described. Results: The study included 255 patients with a mean age of 70 years; 54.9 % were males. Most common comorbidities were high blood pressure (58 %), dyslipidemia (42.4 %), diabetes (25.5 %) and obesity (24.3 %). Median number of days from the onset of clinical symptoms prior to hospital admission was seven. Most common manifestations prior to admission were fever (74.5 %), dry cough (61.2 %), malaise (51.8 %) and dyspnea (51.0 %); 19 patients (7.4 %) were admitted to the intensive care unit, where mortality was 50 %; overall mortality was 16.9 %. Conclusions: Our cohort reflects similar characteristics to those of other European series. Mortality was lower than that in similar studies

Influence of coronary artery disease and subclinical atherosclerosis related polymorphisms on the risk of atherosclerosis in rheumatoid arthritis

A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2). In the present study, we assessed the potential association of these polymorphisms with CVD in Southern European RA patients. We also assessed if polymorphisms implicated in the increased risk of subclinical atherosclerosis in non-rheumatic Caucasians (ZHX2, PINX1, SLC17A4, LRIG1 and LDLR) may influence the risk for CVD in RA. 2,609 Spanish patients were genotyped by TaqMan assays. Subclinical atherosclerosis was determined in 1,258 of them by carotid ultrasonography (assessment of carotid intima media thickness and presence/absence of carotid plaques). No statistically significant differences were found when each polymorphism was assessed according to the presence/ absence of cardiovascular events and subclinical atherosclerosis, after adjustment for potential confounder factors. Our results do not show an association between these 15 polymorphisms and atherosclerosis in RA

Demographic and clinical characteristics of the Spanish patients with RA included in the study.

<p>RA: Rheumatoid arthritis; SD: Standard deviation; Anti-CCP antibodies: Anti-cyclic citrullinated peptide antibodies.</p><p>*At least two determinations were required for analysis of this result.</p><p>** Extra-articular manifestations of the disease (if RA patients experienced at least one of the following manifestations: nodular disease, Felty’s syndrome, pulmonary fibrosis, rheumatoid vasculitis, or secondary Sjögren’s syndrome) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143153#pone.0143153.ref002" target="_blank">2</a>].</p><p>***At the time of assessment.</p><p>Demographic and clinical characteristics of the Spanish patients with RA included in the study.</p

Influence of elevated-CRP levelrelated polymorphisms in nonrheumatic Caucasians on the risk of subclinical atherosclerosis and cardiovascular disease in rheumatoid arthritis

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA

Identification of a 3'-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study

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] ? 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.This study was supported by European Union FEDER funds and “Fondo de Investigación Sanitaria” (grants PI06/0024, PS09/00748, PI12/00060 and PI15/00525) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Programs RD12/0009 and RD16/0012 (RIER) from ISCIII, and in part by grants from the European IMI BTCure Program. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, “Investing in your future”) (grant CP16/00033). FDC was supported by the “Ramón y Cajal” programme of the Spanish Ministry of Economy and Competitiveness through the grant RYC-2014-16458. FG is a recipient of a Sara Borrell post-doctoral fellowship from the ISCIII, co-funded by the ESF (grant CD15/00095). SR-M is supported by funds of the RETICS Program (RIER) RD16/0012/0009 (ISCIII, co-funded by ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ERDF)