PMID- 26386125 OWN - NLM STAT- MEDLINE DCOM- 20160406 LR - 20240228 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 75 IP - 1 DP - 2016 Jan TI - Loci associated with N-glycosylation of human IgG are not associated with rheumatoid arthritis: a Mendelian randomisation study. PG - 317-20 LID - 10.1136/annrheumdis-2014-207210 [doi] AB - OBJECTIVES: 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=6.92x10(-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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - Yarwood, Annie AU - Yarwood A AD - 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. FAU - Viatte, Sebastien AU - Viatte S AUID- ORCID: 0000-0001-6471-3358 AD - 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. FAU - Okada, Yukinori AU - Okada Y AD - 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. FAU - Plenge, Robert AU - Plenge R AD - Merck Research Laboratories, Merck & Co. Inc., Boston, Massachusetts, USA. FAU - Yamamoto, Kazuhiko AU - Yamamoto K AD - 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. CN - BRAGGSS, RACI FAU - Barton, Anne AU - Barton A AD - 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. FAU - Symmons, Deborah AU - Symmons D AD - 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. FAU - Raychaudhuri, Soumya AU - Raychaudhuri S AD - 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. FAU - Klareskog, Lars AU - Klareskog L AD - Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden. FAU - Gregersen, Peter AU - Gregersen P AD - The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA. FAU - Worthington, Jane AU - Worthington J AD - 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. FAU - Eyre, Steve AU - Eyre S AD - 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. LA - eng GR - MR/K015346/1/MRC_/Medical Research Council/United Kingdom GR - MANMKBRU-2012-1/DH_/Department of Health/United Kingdom GR - R01 AR063759/AR/NIAMS NIH HHS/United States GR - 20385/ARC_/Arthritis Research UK/United Kingdom GR - 20380/ARC_/Arthritis Research UK/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't DEP - 20150917 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (Biological Products) RN - 0 (Immunoglobulin G) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (glycosylated IgG) SB - IM MH - Arthritis, Rheumatoid/drug therapy/*genetics/immunology MH - Biological Products/therapeutic use MH - Case-Control Studies MH - Genetic Loci MH - Genetic Predisposition to Disease MH - Glycosylation MH - Humans MH - Immunoglobulin G/*genetics MH - Linkage Disequilibrium MH - Mendelian Randomization Analysis/methods MH - Polymorphism, Single Nucleotide MH - Severity of Illness Index MH - Treatment Outcome MH - Tumor Necrosis Factor-alpha/antagonists & inhibitors PMC - PMC4717396 OTO - NOTNLM OT - Autoimmunity OT - Gene Polymorphism OT - Rheumatoid Arthritis EDAT- 2015/09/20 06:00 MHDA- 2016/04/07 06:00 PMCR- 2016/01/19 CRDT- 2015/09/20 06:00 PHST- 2014/12/23 00:00 [received] PHST- 2015/07/14 00:00 [accepted] PHST- 2015/09/20 06:00 [entrez] PHST- 2015/09/20 06:00 [pubmed] PHST- 2016/04/07 06:00 [medline] PHST- 2016/01/19 00:00 [pmc-release] AID - annrheumdis-2014-207210 [pii] AID - 10.1136/annrheumdis-2014-207210 [doi] PST - ppublish SO - Ann Rheum Dis. 2016 Jan;75(1):317-20. doi: 10.1136/annrheumdis-2014-207210. Epub 2015 Sep 17.