Genetic variation in TIMP1 but not MMPs predict excess FEV1 decline in two general population-based cohorts

Respir Res. 2011 Apr 27;12(1):57. doi: 10.1186/1465-9921-12-57.

Abstract

Background: An imbalance in matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to chronic obstructive pulmonary disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking.

Methods: We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n=1152).

Results: MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p=0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p=0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development.

Conclusions: We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • European Continental Ancestry Group / genetics
  • Female
  • Forced Expiratory Volume / genetics*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Linear Models
  • Lung / physiopathology*
  • Male
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 12 / genetics
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinases, Secreted / genetics*
  • Middle Aged
  • Netherlands
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Pulmonary Disease, Chronic Obstructive / enzymology
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Risk Assessment
  • Risk Factors
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*

Substances

  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinases, Secreted
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • MMP12 protein, human
  • Matrix Metalloproteinase 12
  • MMP1 protein, human
  • Matrix Metalloproteinase 1