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Ann Rheum Dis. 2015 Apr;74(4):762-8. doi: 10.1136/annrheumdis-2013-204173. Epub 2013 Dec 13.

Genetic risk scores and number of autoantibodies in patients with rheumatoid arthritis.

Author information

1
Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
2
Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.
3
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.
4
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
5
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
6
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
7
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
8
Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
9
Departments of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
10
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
11
Department of Rheumatology, Hospital Marques de Valdecilla, Santander, Spain.
12
Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain.
13
Department of Rheumatology, Hospital La Paz, Madrid, Spain.

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).

METHOD:

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.

KEYWORDS:

ACPA; RF; antibodies; genetics; rheumatoid arthritis

PMID:
24336335
DOI:
10.1136/annrheumdis-2013-204173
[Indexed for MEDLINE]
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