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.
