Matrix metalloproteinase gene polymorphisms and susceptibility to systemic sclerosis

Abstract

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 2 T.F. Rech et al. Genetics and Molecular Research 15 (4): gmr15049077(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.

The association between MMP-1 gene rs1799750 polymorphism and knee osteoarthritis risk

“…They also indicated that rs1799750 polymorphism increased the MMP1 expression in vitro [ 19 ]. Rech et al [ 20 ] uncovered that MMP-1 gene variants were associated with systemic sclerosis. A host of studies also demonstrated that MMP-1 gene rs1799750 polymorphism was related to cancer susceptibility, such as leukemia [ 21 ] and gastric cancer [ 22 ].…”

Characteristics of Japanese patients with systemic sclerosis complicated with calcinosis

“…Several studies focused on the genetic factors. Associations of HLA DRB104 and single nucleotide polymorphisms of matrix metalloprotease 3 that involve extracellular matrix protein deposition have been reported, as have single nucleotide polymorphisms of the plasma protein α‐2‐HS‐glycoprotein displaying interaction with calcium phosphate, with ectopic vascular calcification inhibition and calcinosis in SSc 9 …”

“…The significant component of calcinosis in SSc is calcium hydroxyapatite 3 . Several mechanisms of calcinosis in SSc have been reported: chronic hypoxemia, 4 repetitive injury due to peripheral circulatory insufficiency, impaired limb extension caused by skin sclerosis, local tissue structural damage, 5 genetic factors, 6‐9 increased production of tumor necrosis factor‐α, interleukin‐1, interleukin‐6, and other inflammation‐induced cytokines, 10 and imbalance between hypoxia‐induced angiogenic factors (such as vascular endothelial growth factor and platelet‐derived growth factor) and anti‐angiogenic factors (such as angiostatin and endostatin) 11 . Clinically, risk factors for calcinosis in SSc have been reported to be associated with longer duration of morbidity, 12 anti‐centromere antibody positivity, 2 limited‐type SSc, 2 and skin ulcers 13 .…”

Prediction of severity and subtype of fibrosing disease using model informed by inflammation and extracellular matrix gene index

“…Along with several other MMPs and their inhibitors, levels of MMP-1 show close association with SSc, and we found that gene expression differed between dSSc and lSSc patient profiles ( Fig 6 ). Serum levels of MMPs are increased in a subset of patients [ 57 ], polymorphisms are associated with various clinical features of disease [ 58 ], and anti-MMP1 antibodies are elevated in lSSc patients [ 59 ]. To our knowledge, this is the first study indicating that transcript levels of MMP1 may differ between lSSc and dSSc patients.…”