title: MHC associations with clinical and autoantibody manifestations in European SLE.
abstract: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: D L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: M M A
authors.initials: MM
authors.lastname: Fernando
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Taylor
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Chung
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nititham
authors.affiliation: 1] Department of Human DNA Variability, GENYO, Centro de Genómica e Investigación Oncológica Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain [2] Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma, OK, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Barcellos
authors.affiliation: Immunology Biomarkers Group, Genentech, South San Francisco, CA, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: Department of Neurology, Yale School of Medicine, Connecticut, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cotsapas
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma, OK, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Immunology Biomarkers Group, Genentech, South San Francisco, CA, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Rheumatology Service, Hospital Provincial de Rosario, Sanatorio Parque, Rosario, Argentina.
authors.forename: B A
authors.initials: BA
authors.lastname: Pons-Estel
authors.affiliation: The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Immunology Biomarkers Group, Genentech, South San Francisco, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hom
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Noble
authors.affiliation: Department of Medicine, Université de Montréal and Research Center, Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: University of California Davis, Davis, CA, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
mesh_terms: D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D005060:Europe; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008957:Models, Genetic
chemical_list: D001323:Autoantibodies; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen