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Six genes linked to preterm birth in landmark study

Based on data from more than 50,000 women, the discovery may help prevent preterm births...

The study is based on data from more than 50,000 women, published in The New England Journal of Medicine, and could lead to new ways to prevent the leading cause of infant mortality. A massive DNA analysis of pregnant women has identified six gene regions that influence the length of pregnancy and the timing of birth.

Preterm birth is defined as any birth occurring before 37 weeks of pregnancy. In addition to the risk of death, babies who survive an early birth often face serious, lifelong health problems, including chronic lung disease, vision and hearing impairment, cerebral palsy, and neurodevelopmental disabilities. The scientific world has been hunting for the causes of preterm birth for decades.

"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," says Dr. Louis J. Muglia, MD, PhD, Co-Director of the Perinatal Institute, Division of Neonatology at the Cincinnati Children's Hospital, Cincinatti, Ohio, and Director of the Center for Prevention of Preterm Birth, and Professor at UC Department of Pediatrics.
"This is a very exciting discovery that can be expected to lead to the development of new treatments to prevent pregnant women from going into labor too soon and to give more babies a healthy start in life."

Stacey D. Stewart, President, March of Dimes.

Identifying the biologic causes of preterm birth is needed to reach the March of Dimes 5.5 percent goal for preterm births in the United States by 2030. According to Dr. Muglia, the current study has assembled genomic data five times greater than any previous study of pregnancy and preterm birth. The findings are based heavily on more than 44,000 women who provided saliva samples to 23andMe, answered questions about their past pregnancies, and allowed their genetic information to be anonymously analyzed for science. Other crucial data sets include more than 8,000 Nordic women gathered through the Mother Child Cohort of Norway (MoBa), The Finnish Birth Cohort (FIN), and the Danish National Birth Cohort (DNBC).

"In the past year, there have been several successful large genome-wide association studies of reproductive behaviors; in that context, I think this study is particularly important because of the immediate clinical relevance of gestational timing," says David Hinds, PhD, 23andMe Principal Scientist and Statistical Geneticist, who helped to co-author the paper. "This work shows that genetics can improve our understanding of variation in timing."

"These are exciting findings that could play a key role in reducing newborn deaths and giving every child the chance to grow up smart and strong," says Trevor Mundel, President of the Global Health Division of the Bill & Melinda Gates Foundation. "Not only did the study reveal several genes linked to pre-term birth, it also identified a simple, low-cost solution - selenium supplements for expectant mothers - that, if confirmed, could save thousands of lives. It's a great example of the power of public-private partnership."

This is a beginning point. The six gene areas identified by the project serve as a launching platform for deeper research, some of which has already begun. Potential diagnostic tests, new medications, improved dietary supplements or other changes that could help more women have full-term pregnancies will require several more years of study, the authors say. One of the gene areas identified suggests that cells within the lining of the uterus play a larger-than-expected role in the length of pregnancy, which in turn provides a new target for medications to help prevent preterm birth.
Another newly identified gene area raises important questions about how a lack of selenium - a common dietary mineral found in some nuts, certain green vegetables, liver and other meats - might affect preterm birth risk. People living in regions with low selenium in soil and diet, and people in the U.S. who live in low-income "food deserts" are most at risk of having a lack of selenium in their diets.

In the months and years to come, much more research will be conducted to build upon today's findings. For example, work is underway to launch studies in Africa and Asia to determine how precisely the gene associations found in this study apply to non-European populations. Planning work has started to conduct more-specific testing of selenium levels in pregnant women in low-income nations and areas within the United States.

Dr. Muglia noted that the findings will also be part of a March of Dimes Prematurity Research Center database that will allow researchers to study the importance of these genes in the context of other factors in preterm birth now under investigation. Including the following:

• The microbiome and inflammation/infection
• Structural integrity of cervix and uterine pacemakers driving contractions
• The fetal-maternal signaling to initiate labor
• Nutrition and mitochondria
• The molecular basis of social determinants of preterm birth

Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. Our study shows the utility of combining large samples that have self-reported phenotyping with more modestly sized but precisely phenotyped replication studies to reveal maternal loci associated with gestational duration and preterm birth. With this foundation, we anticipate that larger studies of samples with maternal and fetal genotyping associated with data regarding gestational duration will further refine our understanding of human pregnancy and the risk of adverse pregnancy outcomes.

Other authors of the study: Ge Zhang, M.D., Ph.D., Bjarke Feenstra, Ph.D., Jonas Bacelis, B.S., Xueping Liu, Ph.D., Lisa M. Muglia, Ph.D., Julius Juodakis, B.S., Daniel E. Miller, B.S., Nadia Litterman, Ph.D., Pan-Pan Jiang, Ph.D., Laura Russell, M.S., David A. Hinds, Ph.D., Youna Hu, Ph.D., Matthew T. Weirauch, Ph.D., Xiaoting Chen, Ph.D., Arun R. Chavan, M.Sci., Günter P. Wagner, Ph.D., Mihaela Pavli?ev, Ph.D., Mauris C. Nnamani, Ph.D., Jamie Maziarz, M.Sc., Minna K. Karjalainen, Ph.D., Mika Rämet, M.D., Ph.D., Verena Sengpiel, M.D., Ph.D., Frank Geller, M.Sc., Heather A. Boyd, Ph.D., Aarno Palotie, M.D., Ph.D., Allison Momany, B.S., Bruce Bedell, M.A., Kelli K. Ryckman, Ph.D., Johanna M. Huusko, Ph.D., Carmy R. Forney, B.S., Leah C. Kottyan, Ph.D., Mikko Hallman, M.D., Ph.D., Kari Teramo, M.D., Ph.D., Ellen A. Nohr, Ph.D., George Davey Smith, D.Sc., Mads Melbye, M.D., D.M.Sc., Bo Jacobsson, M.D., Ph.D., and Louis J. Muglia, M.D., Ph.D.

Supported by grants (22-FY15-003, to Dr. Muglia; and 21-FY16-121) from the March of Dimes, grants from the National Institutes of Health, grants (to Drs. Jiang, Hu, Hinds, and Litterman and Ms. Russell) from the Cincinnati Children’s Hospital Medical Center, a grant (to Dr. Muglia) from the Fifth Third Foundation, a grant (OPP1113966, to Dr. Muglia) from the Bill and Melinda Gates Foundation, a grant from the Jane and Aatos Erkko Foundation, grants (FUGE 183220/S10 and FRIMEDKLI-05 ES236011) from the Norwegian Research Council, a grant from the Jane and Dan Olsson Foundations, a grant (ALFGBG-507701) from the Swedish government to researchers in the public health service, and a grant (FP7/2007-2013) from the European Community’s Seventh Framework Program (grant agreement HEALTH-F4-2007-201413). Dr. Wagner is supported by a grant (54860) from the John Templeton Foundation; Dr. Feenstra, by an Oak Foundation fellowship; Dr. Liu, by the Nordic Center of Excellence in Health-Related e-Sciences; the Norwegian Mother and Child Cohort Study, by the Norwegian Ministry of Health and the Ministry of Education and Research, by the National Institute of Environmental Health Sciences (contract no. N01-ES-75558), the National Institute of Neurological Disorders and Stroke (UO1 NS 047537-01 and UO1 NS 047537-06A1), by the Norwegian Research Council/FUGE (151918/S10 and FRI-MEDBIO 249779), and by the Swedish Research Council (2015-02559); Dr. Palotie, by the Academy of Finland; Dr. Ryckman, by the March of Dimes, Bill and Melinda Gates Foundation, and National Institutes of Health; Dr. Chavan and Ms. Maziarz, by the John Templeton Foundation; and Dr. Boyd, by the National Institutes of Health Genes, Environment, and Health Initiative and the Danish Council for Independent Research, Medical Sciences. Support from the Functional Genomics Core at Cincinnati Children’s Hospital Medical Center was made possible through a grant (P30 AR070549) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Jacobsson and Muglia contributed equally to this article.

We thank the participants in the Finnish birth cohort, the Mother Child Cohort of Norway, and the Danish National Birth Cohort (a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation); dbGAP for depositing and hosting the phenotype and genotype data; the research participants and employees of 23andMe; Hugh Taylor of Yale Medical School for providing biopsy samples of endometrial stromal fibroblasts for RNA sequencing; and Gil More, also of Yale Medical School, for providing immortalized human endometrial stromal fibroblasts for chromatin immunoprecipitation sequencing.
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Sep 12, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

Six gene areas are now identified as new ways to prevent preterm birth, the leading cause of death among children under age 5 worldwide. Image credit: Mibebitoprematuro.blogspot

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