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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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Effect of SNPs in TIMP1 on longitudinal decline in FEV1, stratified by sex. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.
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Figure 2: Effect of SNPs in TIMP1 on longitudinal decline in FEV1, stratified by sex. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.

Mentions: The TIMP1 Phe124Phe SNP was associated with excess FEV1 decline in males only (-4.2 ml/yr excess FEV1 decline compared to wild type (p = 0.041, figure 2). We found that the TIMP1 Ile158Ile SNP was associated with excess longitudinal FEV1 decline in both males and females (-30.7 ml/yr respectively -9.5 ml/yr excess FEV1 decline compared to wild type, p = 0.001 and p = 0.031 respectively, figure 2). The minor allele of the Ile158Ile SNP was more prevalent in females with COPD than without COPD: CT genotype, 6.5% and 1.5% respectively, p = 0.051 (table 4). The TIMP1 Phe124Phe SNP was not associated with COPD, although power to detect such an association was low. SNPs in TIMP1 were not associated with level of lung function cross-sectionally.


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 TIMP1 on longitudinal decline in FEV1, stratified by sex. 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 2: Effect of SNPs in TIMP1 on longitudinal decline in FEV1, stratified by sex. Mean adjusted declines in FEV1 (in ml/yr) are shown per genotype; bars represent 95% confidence intervals.
Mentions: The TIMP1 Phe124Phe SNP was associated with excess FEV1 decline in males only (-4.2 ml/yr excess FEV1 decline compared to wild type (p = 0.041, figure 2). We found that the TIMP1 Ile158Ile SNP was associated with excess longitudinal FEV1 decline in both males and females (-30.7 ml/yr respectively -9.5 ml/yr excess FEV1 decline compared to wild type, p = 0.001 and p = 0.031 respectively, figure 2). The minor allele of the Ile158Ile SNP was more prevalent in females with COPD than without COPD: CT genotype, 6.5% and 1.5% respectively, p = 0.051 (table 4). The TIMP1 Phe124Phe SNP was not associated with COPD, although power to detect such an association was low. SNPs in TIMP1 were not associated with level of lung function cross-sectionally.

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