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.

We investigated the association of matrix metalloproteinases, the disintegrin and metalloprotease 33 and the tissue and serum inhibitors of proteinase gene polymorphisms with severe chronic respiratory diseases in Tatar children. We analyzed the case-control data sample from a total of 592 Tatar individuals, consisting of 119 children with chronic bronchitis, 138 with recurrent pneumonia and 335 control children residing in Ufa (Russia). The percentage of heterozygous genotype for the MMP9 (2660A>G) was higher among healthy children (52.54% vs 36.13% in chronic bronchitis patients, P(adj)=0.0033, P(cor)=0.033, odds ratio (OR)=0.51; and 36.96% in recurrent pneumonia group, P(adj)=0.0034, P(cor)=0.034, OR=0.53). The MMP12 (-82A>G) locus was associated with chronic bronchitis in the additive model (P(adj)=0.0091, P(cor)=0.09, OR=0.45, β=-0.798). The relationship between the 6A6A genotype of MMP3 (-1171 5A>6A) (P(adj)=0.0013, P(cor)=0.013, OR=3.91) and the 6A-A haplotype of MMP3 (-1171 5A>6A) and MMP12 (-82A>G) and recurrent pneumonia were unraveled (Padj=0.001, P(cor)=0.01, OR=2.07). This haplotype was also associated with a higher risk of chronic bronchitis (P(adj)=0.0012, P(cor)=0.012, OR=2.15). The TIMP3 (-1296T>C) was associated with recurrent pneumonia in the dominant model (P(adj)=0.0031, P(cor)=0.031, OR=1.91). The MMP9, MMP3 and TIMP3 (tissue inhibitors of matrix metalloproteinases) polymorphisms and MMP3 and MMP12 haplotypes may play a substantial role in susceptibility to severe airway and lung injury in children with chronic bronchitis and recurrent pneumonia.