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

PCR-RFLP analysis was performed for 391 cases and 514 control individuals to analyze the contribution 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 metalloproteinase genes TIMP2 (-418 G > C, rs8179090) and TIMP3 (-1296 T > C, rs9619311) to chronic obstructive pulmonary 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 pulmonary 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 factors for the development and progression of chronic obstructive pulmonary disease; in addition, pathogenetically significant gene-environment interactions were identified. These data contribute to the understanding of hereditary predisposition to chronic obstructive pulmonary disease.