Non-classical circulating monocytes expressing high levels of microsomal prostaglandin E2 synthase-1 tag an aberrant IFN-response in systemic sclerosis

Systemic sclerosis (SSc) is a complex disease that affects the connective tissue, causing fibrosis. SSc patients show altered immune cell composition and activation in the peripheral blood (PB). PB monocytes (Mos) are recruited into tissues where they differentiate into macrophages, which are directly involved in fibrosis. To understand the role of CD14+ PB Mos in SSc, a single-cell transcriptome analysis (scRNA-seq) was conducted on 8 SSc patients and 8 controls. Using unsupervised clustering methods, CD14+ cells were assigned to 11 clusters, which added granularity to the known monocyte subsets: classical (cMos), intermediate (iMos) and non-classical Mos (ncMos) or type 2 dendritic cells. NcMos were significantly overrepresented in SSc patients and showed an active IFN-signature and increased expression levels of PTGES, in addition to monocyte motility and adhesion markers. We identified a SSc-related cluster of IRF7+ STAT1+ iMos with an aberrant IFN-response. Finally, a depletion of M2 polarised cMos in SSc was observed. Our results highlighted the potential of PB Mos as biomarkers for SSc and provided new possibilities for putative drug targets for modulating the innate immune response in SSc.Funding for open access charge: Universidad de Granada / CBUA This work was supported by the grant P18-RT-4442 funded by Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía. “Red de Investigación Cooperativa Orientada a Resultados en Salud'' (RICOR, RD21/0002/003). 115565. LBC was supported by the Spanish Ministry of Science and Innovation through the Juan de la Cierva Incorporación' program (Grant ref. IJC2018-038026-I, funded by MCIN/AEI/10.13039/501,100,011,033), which includes FEDER funds. MAH is a recipient of a Miguel Servet fellowship (CP21/00132) from the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). GV-M was funded by the Grant PRE2019-087586 funded by MCIN/AEI/10.13039/501,100,011,033 and by “ESF Investing in your future”

Limitaciones a la libre circulación de trabajadores: Especial referencia al concepto de función pública

After the Treaty establishing the European Community, article 39 recognized the free movement of workers with the prohibition of discrimination based on the nationality of another Member State, except in the case of public administrations. This article analyzes how European jurisprudence has followed a definition of public administration and public employment to overcome this obstacle or limit to the free movement of workers in certain cases.Tras el Tratado Constitutivo de la Comunidad Europea se reconoció en su artículo 39 la libre circulación de trabajadores con prohibición de discriminación por razón de nacionalidad de otro Estado miembro, salvo en el caso de las Administraciones públicas. El presente artículo analiza cómo la jurisprudencia europea ha ido conformando una definición de Administración pública y empleo público para salvar ese obstáculo o límite a la libre circulación de trabajadores en determinados supuestos

Administración digital y teletrabajo

This study addresses the evolution of Spanish regulations on teleworking, from the existing regulations prior to the pandemic to the recent reforms of basic regulations on public employment. Beyond this, it exposes, synthesizes, and critically reflects on the elements of change necessary in said regulations to address a phenomenon that, regardless of specific circumstances experienced throughout those months, should imply a cultural and organizational change in our Public Administrations.El presente estudio aborda la evolución de la normativa española sobre teletrabajo, desde la normativa existente con carácter previo a la pandemia, a las recientes reformas de la normativa básica en materia de empleo público. Más allá de ello, expone, sintetiza, y reflexiona críticamente sobre los elementos de cambio necesarios en dicha normativa para abordar un fenómeno que, con independencia de las concretas circunstancias vividas a lo largo de esos meses, debiera implicar un cambio cultural y organizativo de nuestras Administraciones Públicas

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non- HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO).We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.Ministry of Science and Innovation, Spain (MICINN) IJC2018-038026-IEuropean CommissionSpanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation PY20_00212Andalusian Government B-CTS-584-UGR20 B-AGR-658FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y UniversidadesGrant "Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid" PID2020-120157RB-I0

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

Acknowledgements We thank the National DNA Bank Carlos III (University of Salamanca, Spain) for supplying part of the control DNA samples from Spain and all the participants for their essential collaboration. This work was supported by the Spanish Ministry of Science through the Spanish National Plan for Scientific and Technical Research and Innovation (refs. SAF2016-78722-R and PID2020-120157RB-I00), the Andalusian Plan for Research and Innovation (PAIDI 2020) (ref. PY20_00212), and the R+D+i Projects of the FEDER Operational Programme 2020 (ref. B-CTS-584-UGR20). F.D.C. was supported by the “Ramón y Cajal” programme (ref. RYC-2014-16458), and L.B.C. was supported by the Spanish Ministry of Economy and Competitiveness through the “Juan de la Cierva Incorporación” programme (ref. IJC2018-038026-I, funded by MCIN/AEI /10.13039/ 501100011033), all of them including FEDER funds. A.G.J. was funded by MCIN/AEI /10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). A.M.L. is funded by the Portuguese Government through FCT (IF/01262/2014). P.I.M. is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (Projects: UID/BIM/00009/ 2013 and UIDB/UIDP/00009/2020). SLarriba received support from “Instituto de Salud Carlos III” (grant DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe), and from “Generalitat de Catalunya” (grant 2017SGR191). SLarriba is sponsored by the “Researchers Consolidation Programme” from the SNS-Departament de Salut Generalitat de Catalunya (Exp. CES09/ 020). The German cohort was recruited within the Male Reproductive Genomics (MERGE) study and supported by the German Research Foundation Clinical Research Unit ‘Male Germ Cells’ (DFG CRU326, grants to F.T. and J.G.). This article is related to the Ph.D. Doctoral Thesis of Miriam Cerván-Martín (grant ref. BES-2017-081222 funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”).We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRβ1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.Andalusian Plan for Research and InnovationJuan de la Cierva Incorporación IJC2018-038026-IMinistry for Science, Technology and High EducationBES-2017-081222, MCIN/AEI/10.13039/501100011033National Funds IF/01262/2014, PEstC/SAU/LA0003/2013, POCI-01-0145-FEDER-007274, SFRH/BPD/120777/2016PAIDI 2020 PY20_00212R+D+i Projects B-CTS-584-UGR20, RYC-2014-16458Faculty of Science and Engineering, University of Manchester FPU20/02926Deutsche Forschungsgemeinschaft DFG CRU326Fundação para a Ciência e a TecnologiaGeneralitat de Catalunya 2017SGR191Ministerio de Economía y CompetitividadInstituto de Salud Carlos III DTS18/00101Ministerio de Ciencia e InnovaciónEuropean Social Fund UIDB/UIDP/00009/2020European Regional Development FundFundació Catalana de TrasplantamentDepartament de Salut, Generalitat de Catalunya CES09/020Programa Operacional Temático Factores de CompetitividadeSpanish National Plan for Scientific and Technical Research and Innovation PID2020-120157RB-I00, SAF2016-78722-

The Effect of Body Fat Distribution on Systemic Sclerosis

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genomewide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.MCIN/AEI RTI2018101332-B-100 IJC2018-038026-I IJC2019-040080-I PRE2019-087586"ERDF A way of making Europe" - European UnionRed de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013ESF Investing in your futur

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020) PY20_00212 P20_00583Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation SAF2016-78722-R PID2020-120157RB-I00Proyectos I + D + i del Programa Operativo FEDER 2020 B-CTS-584-UGR20 B-CTS-260-UGR20Spanish Government RYC-2014-16458Spanish Ministry of Economy and Competitiveness through the "Juan de la Cierva Incorporacion" program (MCIN/AEI) IJC2018038026-IEuropean CommissionMCIN/AEIFSE "El FSE invierte en tu futuro" FPU20/02926 BES-2017-081222Portuguese Foundation for Science and Technology (FCT) - European Social Funds (COMPETE-FEDER) Portuguese Foundation for Science and Technology IF/01262/2014FCT from the Portuguese State Budget of the Ministry for Science, Technology and High Education SFRH/BPD/120777/2016European Social Fund through the Programa Operacional do Capital HumanoPortuguese Foundation for Science and Technology European Commission UID/BIM/00009/2013 UIDB/UIDP/00009/2020Instituto de Salud Carlos III (FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe) DTS18/00101Generalitat de Catalunya 2017SGR191SNS-Dpt. Salut Generalitat de Catalunya CES09/020 MCIN/AEI BES-2017-081222 PEstC/SAU/LA0003/2013 POCI-01-0145-FEDER-00727

Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.This research was supported in part by a number of funding sources. This research uses resources provided by the Genetic Association Information Network (GAIN), obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2; samples and associated phenotype data for this study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL, USA). Fulbright Canada, the Weston Foundation, and Brain Canada through the Canada Brain Research Fund—a public-private partnership established by the Government of Canada (to J.G.P.); the National Research Foundation of Korea (NRF) [grant 2016R1C1B2013126 to B.H.] and the Bio & Medical Technology Development Program of the NRF [grant 2017M3A9B6061852 to B.H.] funded by the Korean government, Ministry of Science and ICT; the Finnish Cultural Foundation and Academy of Finland [grant 309643 to H.M.O.]; the Spanish Ministry of Economy and Competitiveness and P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) [grant SAF2015-66761-P to J.M.]; the US National Institutes of Health (NIH) [grants R01AR045584, R01AR056292, X01HG007484 and P30AR057212 to Y.J., S.A.S. and R.S.]; the US NIH [grants N01AR02251 and R01AR05528 to M.D.M.]; the US NIH [grants 1R01AR063759, 1R01AR062886, 1UH2AR067677-01 and U19AI111224-01 to S.R.] and Doris Duke Charitable Foundation [grant 2013097 to S.R.]. Funding for the GAIN schizophrenia sample was provided by the US NIH [grants R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469 and U01 MH79470] and the genotyping of samples was provided through GAIN. The funding sources did not influence the study design, data analysis or writing of this manuscript

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc