The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function.
The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.
Joos
Ladina
L
University of British Columbia McDonald Research Laboratories/iCAPTURE Center, St Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
He
Jian-Qing
JQ
Shepherdson
Megan B
MB
Connett
John E
JE
Anthonisen
Nicholas R
NR
Paré
Peter D
PD
Sandford
Andrew J
AJ
D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects / Q000503:physiopathology
D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1