Association of Chondromodulin-II Val58Ile Polymorphism with Radiographic Joint Destruction in Rheumatoid Arthritis

JUERGEN GRAESSLER, MICHAEL VERLOHREN, ANETT GRAESSLER, ASTRID ZEISSIG, EBERHARD KUHLISCH, STEFFI KOPPRASCH, and HANS-EGBERT SCHROEDER

ABSTRACT.

Objective. Chondromodulin-II (ChM-II) is a cartilage-derived protein involved in cartilage and bone repair. A study of Japanese patients with rheumatoid arthritis (RA) implicated an association between a 172G ® A (Val58Ile) polymorphism and radiographic damage. We analyzed ChM-II for polymorphisms and investigated the association with radiographically assessed joint destruction in German patients with RA. Possible interactions with the shared epitope (SE) were examined.

Methods. DNA samples from 204 patients with RA, 81 patients with osteoarthritis, and 116 patients with gout, serving as controls, were sequenced. Radiographic damage was assessed by modified Larsen score. Allele and genotype frequencies between groups were compared by Cochrane-Armitage trend tests.

Results. Five missense mutations, one silent mutation, and 5 intronic polymorphisms were found. Allele and genotype frequencies were similar in both disease groups. Larsen scores were significantly higher in RA patients carrying the 172AA (Ile/Ile) genotype (Larsen 96.8), than in RA patients with the 172GA (Val/Ile; Larsen 69.5) or 172GG (Val/Val; Larsen 54.8; p = 0.001) genotypes. Odds ratios to develop more severe radiographic joint damage (Larsen score > 90; above 75th percentile) were 4 and 15.5 for the 172GA and 172AA genotypes, respectively. Presence of a 172A allele increased the risk for enhanced radiographic damage 3-fold. SE and ChM-II 172A alleles emerged as 2 independent risk factors. A potentiated interaction of these risk alleles could not be verified.

Conclusion. Our data indicate that ChM-II Val58Ile polymorphism is associated with radiographic progression of joint destruction, particularly in German patients with RA negative for SE. (J Rheumatol 2005;32:1654-61)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
GENETICS
CANDIDATE GENE
CHONDROMODULIN-II
LEUKOCYTE CELL-DERIVED CHEMOTAXIN 2

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From the Department of Pathological Biochemistry, Department of Internal Medicine III, Department of Rheumatology, Department of Radiological Diagnostics, and Institute of Medical Informatics and Biometry, Carl Gustav Carus Medical School, University of Technology Dresden, Dresden, Germany.

J. Graessler, MD; S. Kopprasch, PhD, Department of Pathological Biochemistry; M. Verlohren, MD; A. Graessler, MD; H-E. Schroeder, MD, Professor, Department of Rheumatology; A. Zeissig, MD, Department of Radiological Diagnostics; E. Kuhlisch, Dipl Math, Institute of Medical Informatics and Biometry.

Address reprint requests to Dr. J. Graessler, Department of Pathological Biochemistry, Carl Gustav Carus Medical School, Fetscherstrasse 74, D-01307 Dresden, Germany. E-mail: Juergen.Graessler@mailbox.tu-dresden.de

Accepted for publication April 20, 2005.

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