Collagenase-1 (MMP-1) and HLA-DRB1 gene polymorphisms in rheumatoid arthritis: a prospective longitudinal study.

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic synovitis leading to permanent damage of the joints. Collagenase-1 (MMP-1) is a matrix metalloproteinase involved in articular cartilage degradation. We investigated the association between a biallelic polymorphism in the MMP-1 gene promoter and the susceptibility to, and severity of, RA. We also investigated the association between HLA-DRB1 gene polymorphism and severity of RA. METHODS: One hundred and three patients with early RA were included in this prospective longitudinal study. A radiographic damage score was used to quantify disease severity at baseline and after 4 years of followup. MMP-1 polymorphism genotyping was analyzed using a fluorescent-based polymerase chain reaction (PCR). HLA-DRB1 genotypes were determined by PCR sequence-specific oligonucleotide probes. One hundred and thirty-three healthy individuals were used as controls. RESULTS: MMP-1 allele and genotype frequencies did not differ between RA patients and controls. The radiographic damage or its progression over the 4 years of followup did not differ across MMP-1 genotypes. The radiographic damage score and its progression over the 4 years of followup differed across HLA-DRB1 genotypes. The HLA-DRB I shared epitope +/+ genotype was associated with the highest radiographic damage score and the highest progression, while the shared epitope -/- genotype was associated with the lowest. CONCLUSION: Our results do not support the hypothesis of an association between this particular polymorphism in the MMP-1 gene promoter and susceptibility to, or severity of, RA. This study confirms the previous reports of an association between the HLA-DRB1 gene polymorphism and severity of RA.

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. CONCLUSION: 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.