Genes Behind Preterm Birth Identified

Ricki Lewis, PhD

September 06, 2017

Six genes are associated with gestational duration and/or risk for preterm birth, researchers report in an article published today in the New England Journal of Medicine. The findings may help clinicians identify women at risk for premature birth, and eventually lead to prevention strategies.

"We have known for a long time that preterm birth is a combination of genetic and environmental factors. Previous research has suggested that about 30 to 40 percent of the risk for preterm birth is linked to genetic factors. This new study is the first to provide robust information as to what some of those genetic factors actually are," said study coordinator Louis Muglia, MD, PhD, codirector of the Perinatal Institute at Cincinnati Children's Hospital Medical Center and principal investigator of the March of Dimes Prematurity Research Center-Ohio Collaborative, in a news release.

Nearly a tenth of births in the United States each year are preterm, defined as occurring before 37 weeks' gestation. However, the binary boundary for preterm vs term birth belies a complex biological choreography between fetal maturity and maternal factors. A powerful way to dissect the genetic underpinnings of gestational duration is a genomewide association study (GWAS), which reveals gene variants (alleles) that are significantly overrepresented among women who gave birth prematurely.

Previous GWAS of preterm birth surveyed approximately 1000 cases. However, the larger the data set, the stronger the associations between specific gene variants and the phenotypes. Therefore, in the new study, Ge Zhang, MD, PhD, from the Division of Human Genetics at Cincinnati Children's in Ohio, and an international team analyzed four cohorts encompassing more than 50,000 women.

The initial "discovery" data set included 43,568 women who had provided saliva samples and information about their pregnancy histories to the direct-to-consumer genetic testing company 23andMe and who did not have a medical condition known to cause preterm birth. Single nucleotide polymorphisms (single-base sites that vary among individuals, also called SNPs) were identified across these women and then compared with "reference" data from 8643 mothers and 4090 infants collected from three Nordic birth studies.

The researchers then compared their results with the GWAS Catalog (a database of all published GWAS) and the GTEx20 database, which stores information on gene expression patterns.

Of the 43,568 women who had used 23andMe, 37,803 (86.8%) delivered at term (37-42 weeks), 3331 (7.6%) delivered preterm (<37 weeks), and 2434 (5.6%) delivered postterm (>42 weeks).

Dr Zhang and colleagues evaluated 15,635,593 SNPs. The associations that emerged suggested candidate genes that could be further examined to look for possible biological mechanism linking the genes to pregnancy.

Overall, the discovery cohort revealed three genes (EBF1, EEFSEC, and AGTR2) associated with gestational duration and preterm birth, and three genes (WNT4, ADCY5, and RAP2C) linked to gestational duration but not preterm birth.

Findings in mother–infant pairs from the Nordic cohorts echoed those associations. The correspondence indicates that the genes influence the maternal side of development, rather than fetal factors.

Altogether, the results for the six genes indicate heritability (the genetic component of variance) of 17% for gestational duration and 23% for preterm birth.

The discoveries support past GWAS and reveal specific as well as general possible effects on duration of gestation and risk for preterm birth:

  • ADCY5 (adenylyl cyclase type 5) has previously been associated with birth weight, and RAP2C (an oncogene) has been associated with preterm delivery, in Danish and Norwegian groups.

  • WNT4 (wingless-type MMTV integration site family member 4) is essential in decidualization of the endometrium, implantation, and pregnancy establishment, and one SNP alters the binding of estrogen receptor 1. Past studies implicated WNT4 mutations in müllerian duct abnormalities, primary amenorrhea, and hyperandrogenism.

  • EBF1 (early B-cell factor 1) has been associated with control of blood pressure and carotid artery intima–media thickness.

  • AGTR2 (angiotensin II receptor type 2) controls circulation between the placenta and uterus.

  • EEFSEC (selenocysteine tRNA specific eukaryotic elongation factor) enables incorporation of selenium into proteins that have antioxidant and anti-inflammatory effects, both of which can affect timing of birth.

Limitations of the study include generalizability beyond Europeans, self-reporting, and in some cases, inability to distinguish spontaneous from disease-associated preterm delivery.

The authors note that expanded studies are already underway. Confirmation of the roles of the six genes could lead to tests to identify women at high risk for preterm birth. And some preventive strategies could be simple. "Not only did the study reveal several genes linked to preterm birth, it also identified a simple, low-cost solution — selenium supplements for expectant mothers — that, if confirmed, could save thousands of lives," said Trevor Mundel, president of the Global Health Division of the Bill & Melinda Gates Foundation, in the news release. Selenium deficiency is seen in Malawi, which has the highest risk for preterm birth in the world.

Major funding came from the Gates Foundation, the March of Dimes, Cincinnati Children's, 23andMe, and the National Institute of Child Health and Human Development.

N Engl J Med. Published online September 6, 2017. Full text

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