Your Family Physician

May 12, 2009 (Chicago, Illinois) — Research at the University of Iowa's Carver College of Medicine, in Iowa City, has uncovered a link between prematurity, in particular the premature rupture of membranes (PROM), and a single gene (MMP3).

These findings were presented here at the American College of Obstetricians and Gynecologists (ACOG) 57th Annual Clinical Meeting by lead author Heather Byers, BA, a second-year medical student. The paper by Ms. Byers and colleagues was awarded second place among all papers on current clinical and basic investigation submitted to ACOG’s Committee on Scientific Program. Ms. Byers noted that a single-nucleotide polymorphism was found in the gene MMP3, and described the relevance to meeting attendees.

"MMP3 encodes stromelysin," said Ms. Byers, "and degrades the widest array of extracellular molecules within the decidua, fetal membranes, and cervical extracellular matrix. It plays a key role in the proteolytic pathway, in that it activates other matrix metalloproteinases, including MMP1 and MMP9. It is located in a coding region within a group of 4 amino acids, 3 of which are completely conserved," she noted.

Prematurity is defined as being between 20 and 37 weeks and, according to Ms. Byers, is a complex disease without a clear risk case. "It could be due to the fetus, the mother, or the placenta," she told those attending the conference.

It is estimated that approximately 40% of premature deliveries are linked to genetics and familial clustering, with the woman's greatest risks being a previous preterm delivery, having siblings delivered preterm, or having been a preterm child herself.

The majority of premature deliveries (72%) are spontaneous, according to Ms. Byers, and approximately 30% of those are due to PROM. This study was designed to review 4 candidate genes known to be related to PROM: MMP1, MMP3, MMP9, and SERPINH1.

The fetal membranes amnion and chorion derive their strength from fibrillar collagen, and matrix metalloproteinase enzymes break down collagen in the extracellular matrix and fetal membranes. SERPINH1 is a collagen chaperone protein.

DNA samples from premature cases, term controls, and family members in an Argentine population were collected, genotyped, and analyzed. This was done to identify genetic risk factors that might increase the risk for preterm delivery. The data were then compared with data from Iowa families.

As soon as a baby was identified as premature, DNA was collected from cord blood and from the blood or saliva of the parents and maternal grandparents. Sampling was done in the Maternity Hospital in Tucumán, Argentina. Analysis was performed at the University of Iowa.

For every premature baby, the study identified a sex-matched control from a mother without a history of preterm delivery.

Gene expression was assayed with polymerase chain-reaction technology, and 1536 unique DNA samples from 359 families were reviewed. Data were analyzed using the Family-Based Association Test to measure the fetus effect and distribution of Mendelian transmission.

No significant findings were associated with MMP1, MMP9, or SERPINH1. A single-nucleotide polymorphism was found in MMP3. This had a nonsynonymous amino acid change from glutamate to lysine (i.e., from an uncharged to a charged amino acid). The study authors found this to be significant because MMP3 activates other matrix metalloproteinases and degrades the widest array of extracellular molecules in decidua, fetal membranes, and the cervical extracellular matrix.

Ms. Byers is conducting further analyses to map this particular gene and might then separate the findings into preterm delivery, extreme preterm delivery, and late preterm delivery.

Kurt L. Barnhart, MD, MSCE, member of ACOG's Committee on Scientific Program, commented on the results to Medscape Ob/Gyn & Women's Health. Dr. Barnhart is director of women's health research at the University of Pennsylvania in Bryn Mawr, and served as director, with Janice L. Bacon, MD, of the Papers on Clinical and Basic Investigation session.

"This is a very good example of an early basic-science paper looking into some of the causes of this big problem we have, preterm delivery," Dr. Barnhart said. "It looks at some specific gene alterations for a protein that may have to do with integrity of membrane strength. And it found some associations — people with preterm deliveries have altered genetics for that membrane.

So it's more of opening a link to how we can study this and how it may contribute; it's not purporting to be a clinical test at this point, Dr. Barnhart explained. "It's really opening a window of investigation for us to understand the pathway. Eventually, hopefully, we will have some specific information that can be developed into a diagnostic test," he said.

The study was funded by Carver College of Medicine, the National Institutes of Health, and the March of Dimes. Ms. Byers disclosed no relevant financial relationships.

Source : http://www.medscape.com/viewarticle/702684?sssdmh=dm1.470812&src=nldne