title: Loci associated with N-glycosylation of human IgG are not associated with rheumatoid arthritis: a Mendelian randomisation study.
abstract: OBJECTIVE
  A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity.
  
  
  METHODS
  SNPs showing association with IgG N-glycosylation were analysed for association with RA susceptibility in 14 361 RA cases and 43 923 controls. Five SNPs were tested for association with response to anti-tumour necrosis factor (TNF) therapy in 1081 RA patient samples and for association with radiological disease severity in 342 patients.
  
  
  RESULTS
  Only one SNP (rs9296009) associated with N-glycosylation showed an association (p=6.92×10(-266)) with RA susceptibility, although this was due to linkage disequilibrium with causal human leukocyte antigen (HLA) variants. Four regions of the genome harboured SNPs associated with both traits (shared loci); although statistical analysis indicated that the associations observed for the two traits are independent. No SNPs showed association with response to anti-TNF therapy. One SNP rs12342831 was modestly associated with Larsen score (p=0.05).
  
  
  CONCLUSIONS
  In a large, well-powered cohort of RA patients, we show SNPs driving levels of N-glycosylation have no association with RA susceptibility, indicating colocalisation of associated SNPs are not necessarily indicative of a shared genetic background or a role for glycosylation in disease susceptibility.
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors.forename: Annie
authors.initials: A
authors.lastname: Yarwood
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors.forename: Sebastien
authors.identifier: http://orcid.org/0000-0001-6471-3358
authors.initials: S
authors.lastname: Viatte
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Boston, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Plenge
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.affiliation: NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, Stopford Building, The University of Manchester, Manchester, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Symmons
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Gregersen
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Faculty of Medical and Human Sciences, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D001688:Biological Products / Q000627:therapeutic use; D016022:Case-Control Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics*; D015810:Linkage Disequilibrium; D057182:Mendelian Randomization Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D006023:Glycoproteins
chemical_list: D001688:Biological Products; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; C046179:glycosylated IgG; D006023:Glycoproteins
keywords: Autoimmunity; Gene Polymorphism; Rheumatoid Arthritis