A single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter influences amnion cell MMP-1 expression and risk for preterm premature rupture of the fetal membranes.
Interstitial collagen gives fetal membranes tensile strength, and membrane rupture has been attributed to collagen degradation. A polymorphism at -1607 in the matrix metalloproteinase-1 (MMP-1) promoter (an insertion of a guanine (G)) creates a core Ets binding site and increases promoter activity. We investigated whether this polymorphism is functionally significant for MMP-1 expression in amnion cells and whether it is associated with preterm premature rupture of the membranes (PPROM). The 2G promoter had >2-fold greater activity than the 1G allele in amnion mesenchymal cells and WISH amnion cells. Phorbol 12-myristate 13-acetate (PMA) increased mesenchymal cell nuclear protein binding with greater affinity to the 2G allele. Induction of MMP-1 mRNA by PMA was significantly greater in cells with a 1G/2G or 2G/2G genotype compared with cells homozygous for the 1G allele. When treated with PMA, the 1G/2G and 2G/2G cells produced greater amounts of MMP-1 protein than 1G/1G cells. A significant association was found between fetal carriage of a 2G allele and PPROM. We conclude that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP-1, and that this polymorphism contributes to the risk of PPROM.
Fujimoto
Toshio
T
Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Parry
Samuel
S
Urbanek
Margrit
M
Sammel
Mary
M
Macones
George
G
Kuivaniemi
Helena
H
Romero
Roberto
R
Strauss
Jerome F
JF
D000650:Amnion / Q000201:enzymology*; D044383:Black People; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D008545:Melanoma; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014481:United States; D001741:Black or African American
D017931:DNA Primers; D020781:Matrix Metalloproteinase 1