Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
Martin Kerick,Marialbert Acosta-Herrera,Carmen Pilar Simeón-Aznar,José Luis Callejas,Shervin Assassi,Patricia Carreira,Ivan Castellví,R Ríos,Rosa García Portales,Antonio Fernández-Nebro,Francisco J. García-Hernández,Maria Angeles Aguirre,Benjamín Fernández-Gutiérrez,Luis Rodriguez-Rodriguez,Paloma García de la Peña,E. Vicente,J. L. Andreu,Mónica Fernández Castro,Francisco Javier López-Longo,V. Fonollosa,A. Guillén,Gerard Espinosa,C. Tolosa,A. Pros,Emma Beltrán,Mónica Rodríguez Carballeira,Francisco Javier Narváez,M Rubio Rivas,Vera Ortiz-Santamaria,A. Madroñero,Miguel A. González-Gay,B. Diaz,L. Trapiella,Maria-Victoria Egurbide,P. Fanlo-Mateo,Luis Sáez-Comet,F. Díaz,José Andrés Román-Ivorra,J.J. Alegre Sancho,Mayka Freire,Francisco Javier Blanco Garcia,Natividad Oreiro,A. Kreuter,G. Riemekasten,Paolo Airò,C. Magro,A E Voskuyl,Madelon C. Vonk,Roger Hesselstrand,Annika Nordin,Claudio Lunardi,Armando Gabrielli,Anna-Maria Hoffmann-Vold,J. H. W. Distler,Leonid Padyukov,B. P. C. Koeleman,Susanna Proudman,Mandana Nikpour,Wendy Stevens,Jane Zochling,Joanne Sahhar,Janet Roddy,Peter Nash,Kathleen Tymms,Maureen Rischmueller,Susan C. Lester,Barbara Vigone,Jacques-Olivier Pers,Alain Saraux,Valérie Devauchelle-Pensec,Divi Cornec,Sandrine Jousse-Joulin,Bernard Lauwerys,Julie Ducreux,Anne-Lise Maudoux,Carlos Vasconcelos,A.I. Tavares,Esmeralda Neves,Raquel Faria,Mariana Brandão,Ana Campar,António Marinho,Fátima Farinha,Isabel Almeida,M. Mantecón,Ricardo Blanco Alonso,Alfonso Corrales Martínez,Ricard Cervera,Ignasi Rodríguez-Pintó,Rik Lories,Ellen De Langhe,Doreen Belz,Torsten Witte,N.T. Baerlecken,Georg Stummvoll,Michaela Zauner,Michael Lehner,Eduardo Collantes,Rafaela Ortega-Castro,M. A. Aguirre-Zamorano,Alejandro Escudero-Contreras,M.C. Castro-Villegas,María Concepción Fernández Roldán,Norberto Ortego,Enrique Raya,Inmaculada Jiménez Moleón,Enrique de Ramón,Isabel Díaz Quintero,Pier Luigi Meroni,Maria Gerosa,Tommaso Schioppo,Carolina Artusi,Carlo Chizzolini,A. Zuber,Donatienne Wynar,László Kovács,Attila Balog,Magdolna Deák,Márta Bocskai,Sonja Dulic,Gabriella Kádár,Falk Hiepe,Velia Gerl,Silvia Thiel,M. Maresca,Antonio López-Berrio,Rocío Aguilar-Quesada,Héctor Navarro-Linares,Nicolas Hunzelmann,Gianluca Moroncini,Jeska K de Vries-Bouwstra,Gisela Orozco,Anne Barton,Ariane L. Herrick,Chikashi Terao,Yannick Allanore,Carmen Fonseca,Marta E. Alarcón-Riquelme,Timothy R D J Radstake,Lorenzo Beretta,Christopher P. Denton,Maureen D. Mayes,Javier Martín +142 more
TL;DR: In this paper , the authors investigated the association of complement C4 polymorphisms with systemic sclerosis (SSc) risk and found that higher C4 parity confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk.
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Abstract: Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.
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Citations
Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis
01 Oct 2023
TL;DR: Tyrosine kinases, interferon-1 signaling, IL-6 signaling, endogenous thrombin, peroxisome proliferator-activated receptors, lysophosphatidic acid receptors, and amino acid metabolites are new biomarkers with the potential for developing new therapeutic agents.
Complement-mediated synapse loss in Alzheimer’s disease: mechanisms and involvement of risk factors
Lang Wen,Danlei Bi,Yong Shen +2 more
TL;DR: Recent advances in characterizing complement-mediated synapse loss in AD are reviewed, the underlying mechanisms are summarized, and the possible involvement of AD risk factors such as aging and various risk genes are discussed.
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Sex differences in systemic sclerosis: from pathogenesis to clinical manifestations and treatment
Melpomeni Toitou,Maria Iacovantuono,Carina Mihai,Maria Sole Chimenti,,Oliver Distler,Cosimo Bruni,Muriel Elhai,Melpomeni Toitou,Maria Iacovantuono,Carina Mihai,Maria Sole Chimenti,,Oliver Distler,Cosimo Bruni,Muriel Elhai +13 more
TL;DR: Systemic sclerosis exhibits sex-related disparities in prevalence, clinical features, and outcomes, influenced by biological factors, genetic mechanisms, and sociocultural factors, with implications for clinical management and future research on sex-specific treatment recommendations.
Low C4A copy numbers and higher HERV gene insertion contributes to increased risk of SLE, with absence of association with disease phenotype and disease activity.
Christina Mary Mariaselvam,Gaurav Seth,Chengappa Kavadichanda,Wahid Boukouaci,Ching-Lien Wu,Bruno Costes,Molly Mary Thabah,Rajagopal Krishnamoorthy,Marion Leboyer,V. S. Negi,R. Tamouza +10 more
TL;DR: Low C4A copy number and higher insertion of HERV-K in C4A increases the risk for SLE, and C4 and C4-HERV CNs did not correlate with serum complements, autoantibodies, disease phenotypes and activity in SLE.
The complement inhibitor CD59 is required for GABAergic synaptic transmission in the dentate gyrus.
TL;DR: In this paper , the complement regulator CD59 deficiency impairs GABAergic synaptic transmission in the hippocampal dentate gyrus (DG), which depends on regulation of GABA release triggered by Ca2+ influx through voltage-gated calcium channels.
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