Download PDF
Am J Perinatol
DOI: 10.1055/a-2347-3751
Original Article

Genomic Differences between Spontaneous versus Indicated Extreme Preterm Birth

Namasivayam Ambalavanan 
1   Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
,
C. Michael Cotten
2   Department of Pediatrics, Duke University, Durham, North Carolina
,
Stephen W. Erickson
3   Genomics Research Center, RTI International, Research Triangle Park, North Carolina
,
Ravi Mathur
3   Genomics Research Center, RTI International, Research Triangle Park, North Carolina
,
Dara Torgerson
4   Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California
,
Philip L. Ballard
5   Department of Pediatrics, University of California San Francisco, San Francisco, California
6   National Institute of Child Health and Human Development, Bethesda, Maryland
,
for the Eunice Kennedy Shriver NICHD Neonatal Research Network and the TOLSURF Study Group › Author Affiliations Funding The National Institutes of Health, the Eunice Kennedy Shriver NICHD (grants U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689) and the National Center for Research Resources (General Clinical Research Center grants M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587) provided grant support for the NRN's Glutamine trial which included the Genomic Study through cooperative agreements. In addition, J.C.M. received assistance for the GENEVA study from the National Human Genome Research Institute (U01 HG4423). The validation cohort TOLSURF was supported by the National Institutes of Health/National Heart, Lung and Blood Institute (U01-HL094338 and U01HL094355) and the UCSF Clinical and Translational Sciences Institute (UL1TR000004). ONY, Inc., provided the Infasurf, and IKARIA, Inc., provided the inhaled nitric oxide for TOLSURF.
Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, RTI International had full access to all of the data in the study, and with the NRN Center Principal Investigators, takes responsibility for the integrity of the data and accuracy of the data analysis. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth (PTB) may result from spontaneous preterm labor or preterm premature rupture of membranes or may be indicated due to preeclampsia, eclampsia, hypertension, or other causes. Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme PTB using the neonatal genome.

Study Design We evaluated 523 spontaneous births and 134 indicated births weighing 401 to 1,000 g at birth from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Genomics dataset by genome-wide association study (GWAS) and pathway analysis. The TOLSURF cohort was used to replicate the results.

Results In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p = 1.03E-07) along with many other modest peaks at p = 1–9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being “GO_mf:go_low_density_lipoprotein_particle_receptor_activity” at p = 1.14E-06. However, these results could not be replicated in the TOLSURF cohort.

Conclusion Genomic differences are seen between infants born by spontaneous versus indicated extreme PTB. Due to the limited sample size, there is a need for larger studies.

Key Points

  • Genomic differences are seen between infants born by spontaneous versus indicated very PTB.

  • Future studies with large sample sizes evaluating extreme PTB are necessary.

  • Spontaneous PTB is more common than indicated extreme PTB.

Keywords

prematurity - genomics - preeclampsia - preterm labor

Authors' Contributions

All authors met the American Journal of Perinatology authorship requirements.


N.A.: conception, design of work, drafting the work, acquisition, analysis, and interpretation of data for the work.


C.M.C., S.W.E., R.M., D.T.: design of work, analysis, revising the work critically for important intellectual content, and interpretation of data for the work.


P.L.B.: revising the work critically for important intellectual content, and interpretation of data for the work.


Data Availability

Genotypes and a subset of subject information inclusive of key characteristic and outcome phenotype data have been stored, with no identifying links, in the National Human Genome Research Institute Database of Genotypes and Phenotypes (dbGaP Study Accession: phs000353.v1.p1).


Patient Consent

Written informed consent was obtained from the parent(s) of enrolled infants. The studies were approved by the Institutional Review Boards at the multiple participating centers of the Eunice Kennedy Shriver NICHD NRN and TOLSURF that are listed in the “Acknowledgments” section.


# A complete list of study group members appears in the Acknowledgments.


Supplementary Material



Publication History

Received: 09 February 2024

Accepted: 13 June 2024

Accepted Manuscript online:
18 June 2024

Article published online:
10 July 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Chawanpaiboon S, Vogel JP, Moller AB. et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019; 7 (01) e37-e46
    CrossrefPubMedGoogle Scholar
  • 2 Liu L, Oza S, Hogan D. et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016; 388 (10063): 3027-3035
    CrossrefPubMedGoogle Scholar
  • 3 Frey HA, Klebanoff MA. The epidemiology, etiology, and costs of preterm birth. Semin Fetal Neonatal Med 2016; 21 (02) 68-73
    CrossrefPubMedGoogle Scholar
  • 4 Vogel JP, Chawanpaiboon S, Moller AB, Watananirun K, Bonet M, Lumbiganon P. The global epidemiology of preterm birth. Best Pract Res Clin Obstet Gynaecol 2018; 52: 3-12
    CrossrefPubMedGoogle Scholar
  • 5 Clausson B, Lichtenstein P, Cnattingius S. Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 2000; 107 (03) 375-381
    CrossrefPubMedGoogle Scholar
  • 6 Treloar SA, Macones GA, Mitchell LE, Martin NG. Genetic influences on premature parturition in an Australian twin sample. Twin Res 2000; 3 (02) 80-82
    CrossrefPubMedGoogle Scholar
  • 7 Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am J Epidemiol 2007; 165 (07) 734-741
    CrossrefPubMedGoogle Scholar
  • 8 Liu X, Helenius D, Skotte L. et al. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nat Commun 2019; 10 (01) 3927
    CrossrefPubMedGoogle Scholar
  • 9 Kistka ZA, DeFranco EA, Ligthart L. et al. Heritability of parturition timing: an extended twin design analysis. Am J Obstet Gynecol 2008; 199 (01) 43.e1-43.e5
    CrossrefPubMedGoogle Scholar
  • 10 Wu W, Witherspoon DJ, Fraser A. et al. The heritability of gestational age in a two-million member cohort: implications for spontaneous preterm birth. Hum Genet 2015; 134 (07) 803-808
    CrossrefPubMedGoogle Scholar
  • 11 Ambalavanan N, Cotten CM, Page GP. et al; Genomics and Cytokine Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr 2015; 166 (03) 531-7.e13
    CrossrefPubMedGoogle Scholar
  • 12 Srinivasan L, Page G, Kirpalani H. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Genome-wide association study of sepsis in extremely premature infants. Arch Dis Child Fetal Neonatal Ed 2017; 102 (05) F439-F445
    CrossrefPubMedGoogle Scholar
  • 13 Carlo WA, McDonald SA, Tyson JE. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J Pediatr 2011; 159 (06) 919-25.e3
    CrossrefPubMedGoogle Scholar
  • 14 Purcell S, Neale B, Todd-Brown K. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81 (03) 559-575
    CrossrefPubMedGoogle Scholar
  • 15 de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol 2015; 11 (04) e1004219
    CrossrefPubMedGoogle Scholar
  • 16 Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun 2017; 8 (01) 1826
    CrossrefPubMedGoogle Scholar
  • 17 Ballard RA, Keller RL, Black DM. et al; TOLSURF Study Group. Randomized trial of late surfactant treatment in ventilated preterm infants receiving inhaled nitric oxide. J Pediatr 2016; 168: 23-29.e4
    CrossrefPubMedGoogle Scholar
  • 18 Torgerson DG, Ballard PL, Keller RL. et al; TOLSURF Study Group. Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants. Am J Physiol Lung Cell Mol Physiol 2018; 315 (05) L858-L869
    CrossrefPubMedGoogle Scholar
  • 19 Das S, Forer L, Schönherr S. et al. Next-generation genotype imputation service and methods. Nat Genet 2016; 48 (10) 1284-1287
    CrossrefPubMedGoogle Scholar
  • 20 Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38 (16) e164
    CrossrefPubMedGoogle Scholar
  • 21 Prats-Puig A, Carreras-Badosa G, Bassols J. et al. The placental imprinted DLK1–DIO3 domain: a new link to prenatal and postnatal growth in humans. Am J Obstet Gynecol 2017; 217 (03) 350.e1-350.e13
    CrossrefPubMedGoogle Scholar
  • 22 Rappoport N, Toung J, Hadley D. et al. A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth. Sci Rep 2018; 8 (01) 226
    CrossrefPubMedGoogle Scholar
  • 23 Jarroux J, Morillon A, Pinskaya M. History, discovery, and classification of lncRNAs. Adv Exp Med Biol 2017; 1008: 1-46
    CrossrefPubMedGoogle Scholar
  • 24 Gu Z, Hou Z, Zheng L, Wang X, Wu L, Zhang C. LncRNA DICER1–AS1 promotes the proliferation, invasion and autophagy of osteosarcoma cells via miR-30b/ATG5. Biomed Pharmacother 2018; 104: 110-118
    CrossrefPubMedGoogle Scholar
  • 25 Ebadi N, Ghafouri-Fard S, Taheri M, Arsang-Jang S, Parsa SA, Omrani MD. Dysregulation of autophagy-related lncRNAs in peripheral blood of coronary artery disease patients. Eur J Pharmacol 2020; 867: 172852
    CrossrefPubMedGoogle Scholar
  • 26 Dashti S, Ghafouri-Fard S, Esfandi F, Oskooei VK, Arsang-Jang S, Taheri M. Expression analysis of NF-κB interacting long noncoding RNAs in breast cancer. Exp Mol Pathol 2020; 112: 104359
    CrossrefPubMedGoogle Scholar
  • 27 Lindström TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reproduction 2005; 130 (05) 569-581
    CrossrefPubMedGoogle Scholar
  • 28 Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-pathophysiology and clinical presentations: JACC state-of-the-art review. J Am Coll Cardiol 2020; 76 (14) 1690-1702
    CrossrefPubMedGoogle Scholar
  • 29 Li L, Peng W, Zhou Q, Wan JP, Wang XT, Qi HB. LRP6 regulates Rab7-mediated autophagy through the Wnt/β-catenin pathway to modulate trophoblast cell migration and invasion. J Cell Biochem 2020; 121 (02) 1599-1609
    CrossrefPubMedGoogle Scholar
  • 30 Li L, Wan J, Xue J. et al. Low-density lipoprotein receptor-related protein 6 is essential for trophoblast survival and invasion. Reprod Sci 2019; 26 (01) 35-43
    CrossrefPubMedGoogle Scholar
  • 31 Chatuphonprasert W, Jarukamjorn K, Ellinger I. Physiology and pathophysiology of steroid biosynthesis, transport and metabolism in the human placenta. Front Pharmacol 2018; 9: 1027
    CrossrefPubMedGoogle Scholar
  • 32 Manuck TA. The genomics of prematurity in an era of more precise clinical phenotyping: a review. Semin Fetal Neonatal Med 2016; 21 (02) 89-93
    CrossrefPubMedGoogle Scholar
  • 33 Sirota M, Thomas CG, Liu R. et al; March of Dimes Prematurity Research Centers. Enabling precision medicine in neonatology, an integrated repository for preterm birth research. Sci Data 2018; 5: 180219
    CrossrefPubMedGoogle Scholar
  • 34 Zhang G, Feenstra B, Bacelis J. et al. Genetic associations with gestational duration and spontaneous preterm birth. N Engl J Med 2017; 377 (12) 1156-1167
    CrossrefPubMedGoogle Scholar
  • 35 Bacelis J, Juodakis J, Sengpiel V. et al. Literature-informed analysis of a genome-wide association study of gestational age in Norwegian women and children suggests involvement of inflammatory pathways. PLoS ONE 2016; 11 (08) e0160335
    CrossrefPubMedGoogle Scholar
  • 36 Spiegel AM, Li J, Oehlert JW. et al. A genome-wide analysis of clinical chorioamnionitis among preterm infants. Am J Perinatol 2019; 36 (14) 1453-1458
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Modi BP, Parikh HI, Teves ME. et al. Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth. BMC Med Genet 2018; 19 (01) 181
    CrossrefPubMedGoogle Scholar
  • 38 Romero R, Velez Edwards DR, Kusanovic JP. et al. Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes. Am J Obstet Gynecol 2010; 202 (05) 431.e1-431.e34
    CrossrefPubMedGoogle Scholar
  • 39 Tiensuu H, Haapalainen AM, Karjalainen MK. et al. Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2. PLoS Genet 2019; 15 (06) e1008107
    CrossrefPubMedGoogle Scholar