Promoter variants in tissue inhibitor of metalloproteinase-3 (TIMP-3) protect against susceptibility in pigeon breeders' disease

Abstract

Background: Tissue inhibitors of metalloproteinases (TIMPs) play a major role in extracellular matrix turnover in the lung. However, in chronic lung disorders such as idiopathic pulmonary fibrosis (IPF) and pigeon breeders' disease (PBD), TIMPs may promote an adverse non-degradative environment. We hypothesised that polymorphisms in TIMP-3 could affect susceptibility to IPF and PBD. Methods: Two promoter variants, -915A>G and -1296T>C, were genotyped in 323 healthy subjects, 94 subjects with IPF, 115 with PBD, and 90 exposed to avian antigen but without PBD. The severity of fibrosis in lung tissue and the clinical outcome after 1 year was determined in the PBD group. Results: The variants did not influence susceptibility to IPF, but the rare alleles of both variants appeared to be protective against susceptibility to PBD ( odds ratio ( OR) for carriage of at least one rare allele from either variant 0.48, 95% CI 0.30 to 0.76, p = 0.002). Haplotype analysis of positions -915 and -1296 estimated four haplotypes: AT, GT, AC and GC, respectively. Their frequencies differed overall between subjects with PBD and healthy subjects (p = 0.0049) and this was attributable primarily to the GC haplotype (OR 0.53, 95% CI 0.36 to 0.77, p = 0.001). The severity of fibrosis correlated with poorer outcome in the PBD group (r = 0.73, p<0.01) but no relationship was seen between the GC haplotype and outcome or fibrosis. However, PBD subjects with the GC haplotype did have proportionally fewer lymphocytes in their bronchoalveolar fluid than those with the common AT haplotype (p = 0.029). Conclusions: TIMP-3 variants appear to contribute to susceptibility to PBD. This may be through the inflammatory reaction rather than the fibrotic reaction.