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

van Diemen CC, Postma DS, Siedlinski M, Blokstra A, Smit HA, Boezen HM - Respir. Res. (2011)

Bottom Line: 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).The MMP2 and TIMP1 Ile158Ile associations were not replicated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology, University of Groningen, Groningen, The Netherlands.

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.

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Related in: MedlinePlus

Effect of SNPs in MMP genes on longitudinal decline in FEV1. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.
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Figure 1: Effect of SNPs in MMP genes on longitudinal decline in FEV1. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.

Mentions: MMP2 C-1306T was significantly associated with accelerated longitudinal decline in FEV1 in the total population (TT-genotype -4.0 ml/yr excess decline compared to CC-genotype, p = 0.027, figure 1), and was also associated with a lower mean FEV1 % predicted (CC: 92.5, CT: 93.5, TT: 88.5% predicted; p = 0.013) at the last survey. This association remained significant after adjustment for packyears of smoking in linear regression models. SNPs in MMP1, MMP12 and SNPs and haplotypes in MMP9 were not significantly associated with longitudinal FEV1 decline, level of lung function or presence of COPD (GOLD stage ≥ II) (table 3), although power was limited for the latter. Since smoking upregulates MMP activity [26]. we also analyzed FEV1 decline with respect to interaction of the SNPs and smoking. These interaction-terms were not significant.


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

van Diemen CC, Postma DS, Siedlinski M, Blokstra A, Smit HA, Boezen HM - Respir. Res. (2011)

Effect of SNPs in MMP genes on longitudinal decline in FEV1. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3111362&req=5

Figure 1: Effect of SNPs in MMP genes on longitudinal decline in FEV1. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.
Mentions: MMP2 C-1306T was significantly associated with accelerated longitudinal decline in FEV1 in the total population (TT-genotype -4.0 ml/yr excess decline compared to CC-genotype, p = 0.027, figure 1), and was also associated with a lower mean FEV1 % predicted (CC: 92.5, CT: 93.5, TT: 88.5% predicted; p = 0.013) at the last survey. This association remained significant after adjustment for packyears of smoking in linear regression models. SNPs in MMP1, MMP12 and SNPs and haplotypes in MMP9 were not significantly associated with longitudinal FEV1 decline, level of lung function or presence of COPD (GOLD stage ≥ II) (table 3), although power was limited for the latter. Since smoking upregulates MMP activity [26]. we also analyzed FEV1 decline with respect to interaction of the SNPs and smoking. These interaction-terms were not significant.

Bottom Line: 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).The MMP2 and TIMP1 Ile158Ile associations were not replicated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology, University of Groningen, Groningen, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus