July 28, 2006

Genes’ preterm birth roles studied

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From left, Kelli Ryckman, graduate student, Scott Williams, Ph.D., and Ramkumar Menon, a research scientist at Centennial Medical Center, are studying preterm birth among European-American women.
Photo by Dana Johnson

Genes’ preterm birth roles studied

Nearly half a million babies a year in the United States are born before they should be — and no one really knows why.

Factors like infection, stress, socioeconomic status and previous preterm delivery are associated with increased risk for spontaneous preterm birth, but it's practically impossible to predict who will deliver a baby early.

An international team of investigators is looking for genetic differences that make some women susceptible to preterm labor and delivery.

Scott Williams, Ph.D., associate professor of Medicine at Vanderbilt, and colleagues reported last month in the American Journal of Obstetrics and Gynecology that variations in three genes increased the risk of preterm birth in European-American women. Their study, the first to report an interaction of multiple genes in preterm birth, could lead to a predictive test that would identify patients at risk for preterm birth long before they present with symptoms.

Preterm birth — defined as birth before 37 weeks of gestation — is the single most important risk factor for infant death and long-term health consequences such as cerebral palsy, mental retardation, blindness and respiratory problems.

“Preterm birth is extremely prevalent, with enormous sequelae,” Williams said. “There's good evidence to suggest that even into adulthood, individuals born prematurely are more susceptible to diseases like diabetes and some cancers. And the rate in the United States (about 12 percent) is going up. It's a really important public health issue.”

The current study is part of a large, ongoing effort to examine genetic susceptibility for preterm birth and disparities in the rate of preterm birth for African-Americans and European-Americans. Blacks have a higher rate of premature delivery compared to whites.

The investigators have now amassed a bank of DNA samples from nearly 800 pregnancies — preterm and full-term births — including samples from both the mother and the infant.

“Preterm birth is a fascinating biological problem because there are two individuals contributing to the phenotype,” Williams said. “The mother's genotype, the baby's genotype, and the environmental factors interacting with both of them contribute to a problem that isn't well-resolved.

“If we can figure out who is genetically susceptible to preterm birth, we can treat them earlier in the pregnancy to prevent it.”

Williams noted that there are currently no universally accepted treatments to prevent delivery once labor begins. The hope, he said, is that the genetic findings will point to the underlying signaling pathways and biological mechanisms and allow the development of more effective therapies.

In the current report, the investigators examined genetic variations in five genes involved in inflammation and response to infection. Infection is one of the known risk factors for preterm birth, and increased levels of some pro-inflammatory molecules like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been reported in the fetal membranes and amniotic fluid of women who deliver early.

The sample group included 422 European-American women — 101 preterm delivery and 321 term delivery — recruited through the Perinatal Research Center at Centennial Medical Center in Nashville and Magee Women's Hospital in Pittsburgh. The investigators examined 27 variants in five genes (TNF-alpha, TNF-alpha receptors I and II, IL-6, IL-6 receptor).

None of the individual variants or individual genes had a strong impact alone, Williams said. So the investigators turned to a method developed at Vanderbilt for assessing multi-locus polygenic effects.

Using this approach, they found that three variations, one each in the genes for TNF-alpha, IL-6, and the IL-6 receptor, predisposed the sample group to preterm birth, with a prediction success of 65 percent.

Williams noted that further studies will be required to confirm these predictive gene variants.

“If the model holds up, we could genotype just those three markers and predict 65 percent of the time whether a woman would deliver preterm or full term,” Williams said.

The investigators, in collaboration with a group in the United Kingdom, are finalizing plans to examine 1,536 variations in 128 genes, in fetal and maternal DNA from a total of 5,000 pregnancies.

“After that analysis, we'll have a very large dataset to test if these three interacting variants come out again,” Williams said.

Williams is participating in two international organizations focused on preterm birth. Globally, about 13 million babies are born prematurely each year.

The International Preterm Birth Collaborative (PREBIC) and the Preterm Birth and Genetics International Alliance (PREGENIA) are working to coordinate research efforts aimed at elucidating the causes of preterm birth so that it can be prevented.

Ramkumar Menon from The Perinatal Research Center in Nashville was the first author of the study.

Co-authors include Stephen Fortunato, M.D., also from The Perinatal Research Center, Hyagriv Simhan, M.D., from Magee Women's Hospital in Pittsburgh, Digna Velez, Kelli Ryckman, and Lan Jiang from Vanderbilt, Paul Thorsen, M.D., Ph.D., Ida Vogel, M.D., Ph.D., and Bo Jacobsson, M.D., Ph.D., from the University of Aarhus in Denmark, and Mario Merialdi, M.D., Ph.D., from the World Health Organization.

The research was supported by the Thrasher Research Foundation.