Association of chondromodulin-II Val58Ile polymorphism with radiographic joint destruction in rheumatoid arthritis.
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.


CONCLUSIONS
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.
Graessler
Juergen
J
Department of Pathological Biochemistry, Institute of Medical Informatics and Biometry, Carl Gustav Carus Medical School, University of Technology Dresden, Germany. Juergen.Graessler@mailbox.tu-dresden.de
Verlohren
Michael
M
Graessler
Anett
A
Zeissig
Astrid
A
Kuhlisch
Eberhard
E
Kopprasch
Steffi
S
Schroeder
Hans-Egbert
HE
D000704:Analysis of Variance; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D005858:Germany; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D016017:Odds Ratio; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011336:Probability; D011379:Prognosis; D011859:Radiography; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C103468:LECT2 protein, human