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J Rheumatol. 2015 Aug;42(8):1383-91. doi: 10.3899/jrheum.140741. Epub 2015 Jun 15.

Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study.

Author information

1
From the Department of Rheumatology, and the Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands; the Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, Lund, Sweden, for the BARFOT study group; the Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; Center of Experimental Rheumatology, University Hospital Zurich, Schlieren, Switzerland; the Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.D.P. de Rooy, LLM, MD, PhD, Department of Rheumatology, Leiden University Medical Center; R. Tsonaka, PhD, Department of Medical Statistics, Leiden University Medical Center; M.L. Andersson, BMS, PhD; K. Forslind, Associate Professor, Senior Consultant, Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, for the BARFOT study group; A. Zhernakova, MD, PhD, Department of Rheumatology, Leiden University Medical Center, and Department of Genetics, University Medical Center Groningen and University of Groningen; M. Frank-Bertoncelj, MD, PhD, Center of Experimental Rheumatology, University Hospital Zurich; C.G. de Kovel, PhD; B.P. Koeleman, PhD, Department of Medical Genetics, University Medical Center Utrecht; D.M. van der Heijde, MD, PhD; T.W. Huizinga, MD, PhD; R.E. Toes, PhD, Department of Rheumatology, Leiden University Medical Center; J.J. Houwing-Duistermaat, PhD, PD, Department of Medical Statistics, Leiden University Medical Center; C. Ospelt, MD, PhD, Center of Experimental Rheumatology, University Hospital Zurich; B. Svensson, MD, PhD, Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, for the BARFOT study group; A.H. van der Helm-van Mil, MD, PhD, Department of Rheumatology, Leiden University Medical Center. d.p.c.de_rooy@lumc.nl.
2
From the Department of Rheumatology, and the Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands; the Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, Lund, Sweden, for the BARFOT study group; the Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; Center of Experimental Rheumatology, University Hospital Zurich, Schlieren, Switzerland; the Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.D.P. de Rooy, LLM, MD, PhD, Department of Rheumatology, Leiden University Medical Center; R. Tsonaka, PhD, Department of Medical Statistics, Leiden University Medical Center; M.L. Andersson, BMS, PhD; K. Forslind, Associate Professor, Senior Consultant, Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, for the BARFOT study group; A. Zhernakova, MD, PhD, Department of Rheumatology, Leiden University Medical Center, and Department of Genetics, University Medical Center Groningen and University of Groningen; M. Frank-Bertoncelj, MD, PhD, Center of Experimental Rheumatology, University Hospital Zurich; C.G. de Kovel, PhD; B.P. Koeleman, PhD, Department of Medical Genetics, University Medical Center Utrecht; D.M. van der Heijde, MD, PhD; T.W. Huizinga, MD, PhD; R.E. Toes, PhD, Department of Rheumatology, Leiden University Medical Center; J.J. Houwing-Duistermaat, PhD, PD, Department of Medical Statistics, Leiden University Medical Center; C. Ospelt, MD, PhD, Center of Experimental Rheumatology, University Hospital Zurich; B. Svensson, MD, PhD, Section of Rheumatology at the Institution of Clinical Science, Lund University, Skåne University Hospital, for the BARFOT study group; A.H. van der Helm-van Mil, MD, PhD, Department of Rheumatology, Leiden University Medical Center.

Abstract

OBJECTIVE:

Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients.

METHODS:

A genome-wide association study was done with 262 ACPA-negative patients with early RA included in the Leiden Early Arthritis Clinic and related to radiographic joint destruction over 7 years. Significant single-nucleotide polymorphisms (SNP) were evaluated for association with progression of radiographic joint destruction in 253 ACPA-negative patients with early RA included in the Better Anti-Rheumatic Farmaco Therapy (BARFOT) study. According to the Bonferroni correction of the number of tested SNP, the threshold for significance was p < 2 × 10(-7) in phase 1 and 0.0045 in phase 2. In both cohorts, joint destruction was measured by Sharp/van der Heijde method with good reproducibility.

RESULTS:

Thirty-three SNP associated with severity of joint destruction (p < 2 × 10(-7)) in phase 1. In phase 2, rs2833522 (p = 0.0049) showed borderline significance. A combined analysis of both the Leiden and BARFOT datasets of rs2833522 confirmed this association with joint destruction (p = 3.57 × 10(-9)); the minor allele (A) associated with more severe damage (for instance, after 7 yrs followup, patients carrying AA had 1.22 times more joint damage compared to patients carrying AG and 1.50 times more joint damage than patients carrying GG). In silico analysis using the ENCODE and Ensembl databases showed presence of H3K4me3 histone mark, transcription factors, and long noncoding RNA in the region of rs2833522, an intergenic SNP located between HUNK and SCAF4.

CONCLUSION:

Rs2833522 might be associated with the severity of joint destruction in ACPA-negative RA.

KEYWORDS:

AUTOANTIBODIES; GENETIC STUDIES; JOINT EROSIONS; RHEUMATOID ARTHRITIS

PMID:
26077402
DOI:
10.3899/jrheum.140741
[Indexed for MEDLINE]

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