title: Genetic risk scores and number of autoantibodies in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). Our objective was to examine the combined effect of these associated variants, calculated as a cumulative genetic risk score (GRS) on RA predisposition, as well as the number of autoantibodies (none, one or two present).
  
  
  METHODS
  We calculated four GRSs in 4956 patients and 4983 controls from four European countries. All four scores contained data on 22 non-HLA-risk SNPs, and three scores also contained HLA-DRB1 genotypes but had different HLA typing resolution. Most patients had data on both rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA). The GRSs were standardised (std.GRS) to account for population heterogeneity. Discrimination between patients and controls was examined by receiveroperating characteristics curves, and the four std.GRSs were compared across subgroups according to autoantibody status.
  
  
  RESULTS
  The std.GRS improved its discriminatory ability between patients and controls when HLA-DRB1 data of higher resolution were added to the combined score. Patients had higher mean std.GRS than controls (p=7.9×10(-156)), and this score was significantly higher in patients with autoantibodies (shown for both RF and ACPA). Mean std.GRS was also higher in those with two versus one autoantibody (p=3.7×10(-23)) but was similar in patients without autoantibodies and controls (p=0.12).
  
  
  CONCLUSIONS
  The GRS was associated with the number of autoantibodies and to both RF and ACPA positivity. ACPA play a more important role than RF with regards to the genetic risk profile, but stratification of patients according to both RF and ACPA may optimise future genetic studies.
authors: Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
authors: Marthe T
authors: MT
authors: Maehlen
authors: Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
authors: Inge C
authors: IC
authors: Olsen
authors: Department of EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors: Bettina K
authors: BK
authors: Andreassen
authors: Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
authors: Marte K
authors: MK
authors: Viken
authors: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Xia
authors: X
authors: Jiang
authors: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Lars
authors: L
authors: Alfredsson
authors: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Henrik
authors: H
authors: Källberg
authors: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Boel
authors: B
authors: Brynedal
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Fina
authors: F
authors: Kurreeman
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Nina
authors: N
authors: Daha
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Rene
authors: R
authors: Toes
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors: Alexandra
authors: A
authors: Zhernakova
authors: Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors: Javier
authors: J
authors: Gutierrez-Achury
authors: Departments of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Paul I W
authors: PI
authors: de Bakker
authors: Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
authors: Javier
authors: J
authors: Martin
authors: Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
authors: María
authors: M
authors: Teruel
authors: Department of Rheumatology, Hospital Marques de Valdecilla, Santander, Spain.
authors: Miguel A
authors: MA
authors: Gonzalez-Gay
authors: Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain.
authors: Luis
authors: L
authors: Rodríguez-Rodríguez
authors: Department of Rheumatology, Hospital La Paz, Madrid, Spain.
authors: Alejandro
authors: A
authors: Balsa
authors: Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
authors: Till
authors: T
authors: Uhlig
authors: Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
authors: Tore K
authors: TK
authors: Kvien
authors: Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
authors: Benedicte A
authors: BA
authors: Lie
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000276:immunology; D012217:Rheumatoid Factor / Q000276:immunology; D018570:Risk Assessment; D012307:Risk Factors; D044465:White People
chemical_list: D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor
keywords: ACPA; RF; antibodies; genetics; rheumatoid arthritis