New Gene Identified That May Increase Risk for Preterm Birth

Evolutionary changes that make people uniquely human may have driven human birth timing earlier and can be used to identify genes associated with preterm birth.

Investigators from Vanderbilt University (Nashville, TN, USA), Washington University at St. Louis (MO, USA) , and the University of Helsinki (Finland) reported that variations in a gene with accelerated evolution in humans, the follicle-stimulating hormone receptor (FSHR), may increase a woman's risk for delivering her infant prematurely. The study's findings in the April 14, 2011, open-access journal PLoS Genetics point to a novel biologic pathway that may influence birth timing.

More than half a million babies per year in the US alone--one in eight--are born prematurely (before 37 weeks of gestation). Premature babies face an increased risk of death and serious short-term and long-term medical complications, yet there are no adequate therapies to prevent preterm birth.

"Part of the problem is that we don't understand the fundamental biology of human pregnancy and birth timing,” said Louis Muglia, MD, PhD, professor and vice chair for Research Affairs in the Vanderbilt department of pediatrics. "We don't know if preterm birth in humans is the normal process gone awry, or if it's an entirely distinct process.” Attempts to use animal models to understand human pregnancy have been of limited success, Dr. Muglia said, "The signals that control pregnancy and birth timing in animal models aren't able to be extended to humans; human pregnancy differs from pregnancy in other animal species.”

Dr. Muglia and his colleagues theorized that humans' large heads and narrow pelvises have put pressure on human pregnancy "to adapt and shift the time of birth to the earliest time compatible with optimal survival for both the mom and the fetus.”

To examine whether this notion of evolutionary pressure on birth timing had merit, the researchers compared the length of gestation in humans and nonhuman primates. They demonstrated in the current study that gestation length has decreased in the evolutionary lineage leading to modern humans.

The scientists also compared body and brain sizes at birth in humans and nonhuman primates, in a process called allometric scaling, and demonstrated that human gestation is shorter than would be predicted based on this comparison. "We think there is good evidence that human gestation has been pushed to shorter times, which means there should be a ‘signature' in the human genome--genes with accelerated evolution to accommodate this process,” Dr. Muglia remarked.

Justin Fay, PhD, associate professor of genetics at Washington University and coleader of the study, developed comparative genomic techniques to identify "human accelerated genes”--genes that are most altered in humans compared to six other animals. The researchers identified a set of 450 human accelerated genes and narrowed the list to 150 genes that were plausible candidates for having a role in human pregnancy.

They examined variations in these 150 genes in a cohort of Finnish mothers and found that specific variations in the FSHR gene were more frequent in mothers who had experienced preterm birth. The same variations may also be linked to preterm birth in African-Americans, additional study suggested. The FSHR gene has not previously been implicated in the timing for birth or preterm birth risk.

Studies in larger cohorts could lead to additional accelerated genes with roles in birth timing and provide new targets for therapeutic or preventive measures, Dr. Muglia said. "Ideally we'd like to predict which women are at greatest risk for having preterm birth and be able to prevent it. That would really have an impact on infant mortality and the long-term complications of being born prematurely.”

Related Links:
Vanderbilt University
Washington University in St. Louis
University of Helsinki