Human Molecular Genetics Advance Access originally published online on September 14, 2004
Human Molecular Genetics 2004 13(21):2659-2669; doi:10.1093/hmg/ddh287
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved
Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM)
1Center for Research on Reproduction and Women's Health and 2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USA, 3Perinatology Research Branch, NICHD, Hutzel Hospital, Detroit, MI 48201, USA and 4Department of Anthropology, The Pennsylvania State University, University Park, PA 16802, USA
Received July 23, 2004; Accepted September 3, 2004
Matrix metalloproteinase 8 (MMP8), an enzyme that degrades fibrillar collagens imparting strength to the fetal membranes, is expressed by leukocytes and chorionic cytotrophoblast cells. We identified three single nucleotide polymorphisms (SNPs) at –799C/T, –381A/G and +17C/G from the major transcription start site in the MMP8 gene, and determined the functional significance of these SNPs by analyzing their impact upon MMP8 promoter activity and their association with preterm premature rupture of membranes (PPROM). The minor alleles +17 (G) and –381 (G) were in complete linkage disequilibrium. A promoter fragment containing the three minor alleles had 3-fold greater activity in chorion-like trophoblast cells (BeWo, JEG-3 and HTR-8/SVneo) compared with the major allele promoter construct. Electrophoretic mobility shift assays revealed differences in BeWo nuclear protein binding to oligonucleotides representing the –381 and –799 SNPs, suggesting that the minor alleles have reduced transcription factor binding. A case–control study of African-American neonates using allele-specific primers revealed a statistically significant association between the three minor allele haplotype, which displays the highest MMP8 promoter activity in trophoblast cells, with PPROM with an odds ratio (OR) of 4.63 (P<0.0001), whereas the major allele promoter appeared to be protective (OR=0.52, P<0.0002). None of the minor alleles were individually associated with PPROM. These findings demonstrate the functional significance of SNP haplotypes in the MMP8 gene and associations with obstetrical outcomes.
* To whom correspondence should be addressed at: Center for Research on Reproduction and Women's Health, University of Pennsylvania, 1354 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2158980147; Fax: +1 2155735408; Email: jfs3{at}mail.med.upenn.edu
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