Matrix metalloproteinase gene polymorphisms and susceptibility to systemic sclerosis
T F Rech1, S B C Moraes2, M Bredemeier3
1Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas, RS, Brasil.
Abstract:
The major pathological hallmark of the systemic sclerosis (SSc) is skin and internal organ fibrosis, which results from normal tissue architecture alterations and extracellular matrix (ECM) protein deposition. ECM components are degraded by matrix metalloproteinases (MMP). Promoter region polymorphisms in MMP genes may influence gene expression, resulting in an imbalance between ECM protein production and degradation. Here, we analyzed MMP1 -1607 1G/2G (rs1799750), MMP3 -1171 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms in relation to susceptibility to SSc and its clinical features. The patient group included 98 individuals with longstanding or recently diagnosed disease, meeting the American College of Rheumatology or LeRoy and Medsger criteria for SSc; the control group included 100 healthy blood donors. All participants were of European descent. Genotyping was performed by polymerase chain reaction followed by restriction digestion. Genotype and allele frequencies of MMP polymorphisms were similar between the two groups. In secondary analyses, significantly higher frequency of 1G/2G genotype from MMP1 polymorphism was observed for patients testing positive for antinuclear autoantibodies (P = 0.007), while 1G/1G genotype was associated with interstitial lung disease development (P = 0.018). The 6A/6A genotype from MMP3 polymorphism was absent in patients with calcinosis (P = 0.011), while the MMP3 5A/5A genotype correlated with the presence of anti-topoisomerase I antibodies (P = 0.009) and reduced diffusing capacity for carbon monoxide (P = 0.024). These results suggest that MMP polymorphisms are not associated with SSc susceptibility, although MMP1 and MMP3 variants are associated with specific SSc clinical and laboratory features.
Insights
Matrix metalloproteinase (MMP) gene polymorphisms do not increase systemic sclerosis (SSc) risk. However, MMP1 and MMP3 variants are linked to specific SSc symptoms and laboratory findings, offering insights into disease characteristics.
Area of Science:
- Genetics
- Rheumatology
- Molecular Biology
Background:
- Systemic sclerosis (SSc) is characterized by fibrosis due to altered tissue architecture and extracellular matrix (ECM) deposition.
- Matrix metalloproteinases (MMPs) regulate ECM degradation, and their gene polymorphisms may affect ECM balance.
- Investigating MMP gene promoter polymorphisms can elucidate their role in SSc pathogenesis and clinical manifestations.
Purpose of the Study:
- To analyze the association of MMP1, MMP3, and MMP9 gene polymorphisms with susceptibility to systemic sclerosis (SSc).
- To investigate the relationship between these MMP polymorphisms and specific clinical and laboratory features of SSc.
Main Methods:
- Genotyping of MMP1 (-1607 1G/2G), MMP3 (-1171 5A/6A), and MMP9 (-1562 C/T) polymorphisms using polymerase chain reaction and restriction digestion.
- Comparison of genotype and allele frequencies between 98 SSc patients and 100 healthy controls of European descent.
- Secondary analysis correlating MMP genotypes with SSc clinical features (antinuclear autoantibodies, interstitial lung disease, calcinosis) and laboratory markers (anti-topoisomerase I antibodies, diffusing capacity for carbon monoxide).
Main Results:
- No significant differences in MMP genotype or allele frequencies were found between SSc patients and controls, indicating no association with SSc susceptibility.
- MMP1 1G/2G genotype was more frequent in patients with antinuclear autoantibodies (P=0.007).
- MMP1 1G/1G genotype was linked to interstitial lung disease (P=0.018).
- MMP3 6A/6A genotype was absent in patients with calcinosis (P=0.011).
- MMP3 5A/5A genotype correlated with anti-topoisomerase I antibodies (P=0.009) and reduced diffusing capacity for carbon monoxide (P=0.024).
Conclusions:
- MMP gene polymorphisms are not associated with the overall susceptibility to systemic sclerosis.
- Specific variants in MMP1 and MMP3 genes are associated with distinct clinical and laboratory features of SSc, suggesting a role in disease phenotype.
- These findings highlight potential genetic markers for specific SSc manifestations, warranting further investigation.
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