Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study.
OBJECTIVE
To test the hypothesis of an association between a polymorphism in the matrix metalloproteinase 3 (MMP-3) gene promoter and the susceptibility, severity, and progression of rheumatoid arthritis (RA), and to further document the association between HLA-DRB1 alleles encoding the shared epitope (SE) and the severity and progression of RA.


METHODS
Patients with early RA (n = 103) were included in this prospective study. A total radiographic damage score (TDS; by the Sharp/van der Heijde method) was used to quantify RA severity at baseline and after 4 years of followup. The 5A/6A biallelic polymorphism in the MMP-3 gene promoter was analyzed using fluorescence-based polymerase chain reaction (PCR). HLA-DRB1 genotyping was performed using PCR methods. Control subjects (n = 127) were unrelated healthy individuals.


RESULTS
MMP-3 allele carriage rates and allele and genotype frequencies did not differ between patients and controls. The MMP-3 6A/6A genotype was associated with the highest TDS both at baseline and after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. The DRB1 SE+/+ genotype was associated with the highest TDS after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. Patients homozygous for MMP-3 6A and DRB1 SE had the highest progression of the TDS.


CONCLUSIONS
This study provides the first evidence of an association between a polymorphism in the MMP-3 gene promoter and the severity and progression of RA, but not RA susceptibility. Investigation of this polymorphism could be combined with that of DRB1 gene polymorphism to improve the predictive accuracy and management strategy in early RA.
Constantin
Arnaud
A
Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U395, Toulouse, France.
Lauwers-Cancès
Valérie
V
Navaux
Frédérique
F
Abbal
Michel
M
van Meerwijk
Joost
J
Mazières
Bernard
B
Cambon-Thomsen
Anne
A
Cantagrel
Alain
A
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics*; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D011859:Radiography
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D019278:Matrix Metalloproteinase 3