Association of MMP3, MMP9, ADAM33, and TIMP3 polymorphisms with chronic obstructive pulmonary disease and its progression

Abstract

PCR RFLP analysis was performed for 391 cases and 514 control individuals to analyze the contribu tion of polymorphisms of the matrix metalloproteinase genes MMP1 (-1607 G>GG, rs1799750; -519 A>G, rs494379), MMP2 (-735 C>T, rs2285053), MMP3 (-1171 5A>6A, rs35068180), MMP9 (-1562 C>T, rs3918242; 2660A>G, rs17576), MMP12 (-82 A>G, rs2276109), the disintegrin and metalloproteinase 33 gene ADAM33 (12418 A>G, rs2280091; 13491 C>G, rs2787094), and tissue inhibitors of metalloprotein ase genes TIMP2 (-418 G>C, rs8179090) and TIMP3 (-1296 T>C, rs9619311) to chronic obstructive pul monary disease. Significant association with increased rick of chronic obstructive pulmonary disease was observed for the 6A6A genotype of the MMP3 -1171 5A>6A polymorphism (OR = 2.49, P adj = 0.003979, P cor = 0.0358 adjusted for age, sex, smoke pack years, ethnicity) and for the G-G haplotype of ADAM33 polymorphisms 13491 C>G and 12418 A>G (OR = 0.39, P adj = 0.0012, P cor = 0.006). Significant interactions were detected between the smoking status and ADAM33 12418 A >G (P interact = 0.026) and TIMP3 -1296 T>C (P interact = 0.044). The risk of emphysema was increased in GG homozygotes by ADAM33 13491 C>G and a risk of emphysema was found (OR = 1.74, P adj = 0.013, P cor = 0.117). The severity of chronic obstructive pul monary disease was modified by MMP9 -1562 C>T in the additive model (OR = 1.883, P adj = 0.028, P cor = 0.252). Thus, polymorphisms of MMP3, MMP9, ADAM33, and TIMP3 can be considered important risk fac tors for the development and progression of chronic obstructive pulmonary disease; in addition, pathogenet ically significant gene-environment interactions were identified. These data contribute to the understanding of hereditary predisposition to chronic obstructive pulmonary disease.

Analysis of polymorphisms of genes associated with immune response and tissue remodeling in occupational chronic bronchitis

“…In addition to augmenting inflam matory response and proteolysis in the lungs, ADAM33 is also involved in angiogenesis [32]. Several studies have previously reported that ADAM33 polymor phisms were associated with COPD and bronchial asthma [12,[32][33][34]; our own data confirmed such an association in COPD patients from Bashkortostan [15]. Our results suggest that ADAM33 is an important factor involved in the pathogenesis of respiratory diseases induced by smoking or industrial dust and aerosols.…”

“…TIMP3 is located on chro mosome 22 at site 22q12.1 q13.2; the (-1296T>C) polymorphisms in the gene promoter is thought to affect the level of TIMP3 transcription [13]. It was reported that TIMP3 contributes to the resolution of acute inflammatory damage to lung tissue [41]; the data from our previous studies suggested that TIMP3 locus was associated with COPD and with lingering childhood pneumonia [15,42].…”

“…They play a key role in maintaining the extracellular matrix homeostasis by regulating MMP activity. Polymor phisms of MMP encoding genes and ADAM33 were found to contribute to predisposition to bronchial asthma and COPD [14,15].…”

“…PCR was performed according to the standard proto col using Taq DNA polymerase (Thermo Scientific, Germany) in a T100 TM thermal cycler (Bio Rad Lab oratories, Inc., United States). Primer sequences and allele identification protocols were as described previ ously in [15][16][17]. The results of PCR-RFLP were evaluated by PAGE in 6-8% gels; gels were stained with 0.1 μg/mL ethidium bromide for 15 min and photographed using a UV transilluminator.…”

Effects of cigarette smoke extract on human airway smooth muscle cells in COPD

“…These results indicate that both MMP-3 and -10 may lead to different progression in smokers with COPD. Two genotyping studies indicated that MMP-3 polymorphisms associate with disease progression in COPD [36,37]. Another study showed the expression of the MMP-10 gene was increased in both small airways and the parenchyma surrounding small airways in association with progression of COPD [38].…”