Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genetic variants associated with patent ductus arteriosus in extremely preterm infants

Journal of Perinatology volume 39, pages 401–408 (2019)Cite this article

Subjects

Abstract

Objective:

Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants.

Study design:

Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables.

Results:

SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons.

Conclusion:

We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Park HW, Choi YS, Kim KS, Kim SN. Chorioamnionitis and patent ductus arteriosus: a systematic review and meta-analysis. PLoS ONE. 2015;10:e0138114.

    Article  Google Scholar 

  2. Vucovich MM, Cotton RB, Shelton EL, Goettel JA, Ehinger NJ, Poole SD, et al. Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA. Am J Physiol Heart Circ Physiol. 2014;307:H732–740.

    Article  CAS  Google Scholar 

  3. Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani HM, Nwaesei C, et al. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr. 2006;148:730–4.

    Article  CAS  Google Scholar 

  4. Schena F, Francescato G, Cappelleri A, Picciolli I, Mayer A, Mosca F, et al. Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia. J Pediatr. 2015;166:1488–92.

    Article  Google Scholar 

  5. Slaughter JL, Reagan PB, Bapat RV, Newman TB, Klebanoff MA. Nonsteroidal anti-inflammatory administration and patent ductus arteriosus ligation, a survey of practice preferences at US children’s hospitals. Eur J Pediatr. 2016;175:775–83.

    Article  CAS  Google Scholar 

  6. Lokku A, Mirea L, Lee SK, Shah PS, Canadian Neonatal N. Trends and outcomes of patent ductus arteriosus treatment in very preterm infants in Canada. Am J Perinatol. 2017;34:441–50.

    Article  Google Scholar 

  7. Letshwiti JB, Semberova J, Pichova K, Dempsey EM, Franklin OM, Miletin J. A conservative treatment of patent ductus arteriosus in very low birth weight infants. Early Hum Dev. 2016;104:45–49.

    Article  Google Scholar 

  8. El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr. 2017;176:233–40.

    Article  CAS  Google Scholar 

  9. Bhandari V, Zhou G, Bizzarro MJ, Buhimschi C, Hussain N, Gruen JR, et al. Genetic contribution to patent ductus arteriosus in the premature newborn. Pediatrics. 2009;123:669–73.

    Article  Google Scholar 

  10. Lavoie PM, Pham C, Jang KL. Heritability of hemodynamically significant patent ductus arteriosus persistence in prematurely born infants. Pediatric Academic Societies’ Annual Meeting, Honolulu; 2008. p. E-PAS2008:634835.634834.

  11. Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, et al. Determination of genetic predisposition to patent ductus arteriosus in preterm infants. Pediatrics. 2009;123:1116–23.

    Article  Google Scholar 

  12. Treszl A, Szabo M, Dunai G, Nobilis A, Kocsis I, Machay T, et al. Angiotensin II type 1 receptor A1166C polymorphism and prophylactic indomethacin treatment induced ductus arteriosus closure in very low birth weight neonates. Pediatr Res. 2003;54:753–5.

    Article  CAS  Google Scholar 

  13. Chao CS, Wei J, Huang HW, Yang SC. Correlation between methyltetrahydrofolate reductase (MTHFR) polymorphisms and isolated patent ductus arteriosus in Taiwan. Heart Lung Circ. 2014;23:655–60.

    Article  Google Scholar 

  14. Patel PM, Momany AM, Schaa KL, Romitti PA, Druschel C, Cooper ME, et al. Genetic modifiers of patent ductus arteriosus in term infants. J Pediatr. 2016;176:57–61.

    Article  Google Scholar 

  15. Carlo WA, McDonald SA, Tyson JE, Stoll BJ, Ehrenkranz RA, Shankaran S, et al. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J Pediatr. 2011;159:919–25 e913.

    Article  CAS  Google Scholar 

  16. Hartnett ME, Morrison MA, Smith S, Yanovitch TL, Young TL, Colaizy T, et al. Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants. Invest Ophthalmol Vis Sci. 2014;55:6194–203.

    Article  Google Scholar 

  17. Ment LR, Aden U, Bauer CR, Bada HS, Carlo WA, Kaiser JR, et al. Genes and environment in neonatal intraventricular hemorrhage. Semin Perinatol. 2015;39:592–603.

    Article  Google Scholar 

  18. Ambalavanan N, Cotten CM, Page GP, Carlo WA, Murray JC, Bhattacharya S, et al. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr. 2015;166:531–7 e513.

    Article  CAS  Google Scholar 

  19. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  20. Boghossian NS, Geraci M, Edwards EM, Horbar JD. Morbidity and mortality in small for gestational age infants at 22 to 29 weeks’ gestation. Pediatrics. 2018;141:e20172533.

    Article  Google Scholar 

  21. De Jesus LC, Pappas A, Shankaran S, Li L, Das A, Bell EF, et al. Outcomes of small for gestational age infants born at <27 weeks’ gestation. J Pediatr. 2013;163:55–60 e51-53.

    Article  Google Scholar 

  22. Waleh N, Hodnick R, Jhaveri N, McConaghy S, Dagle J, Seidner S, et al. Patterns of gene expression in the ductus arteriosus are related to environmental and genetic risk factors for persistent ductus patency. Pediatr Res. 2010;68:292–7.

    Article  Google Scholar 

  23. Ivey KN, Sutcliffe D, Richardson J, Clyman RI, Garcia JA, Srivastava D. Transcriptional regulation during development of the ductus arteriosus. Circ Res. 2008;103:388–95.

    Article  CAS  Google Scholar 

  24. Satoda M, Pierpont ME, Diaz GA, Bornemeier RA, Gelb BD. Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21. Circulation. 1999;99:3036–42.

    Article  CAS  Google Scholar 

  25. Sodini D, Baragatti B, Barogi S, Laubach VE, Coceani F. Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouse. Br J Pharmacol. 2008;153:1631–40.

    Article  CAS  Google Scholar 

  26. Majed BH, Khalil RA. Molecular mechanisms regulating the vascular prostacyclin pathways and their adaptation during pregnancy and in the newborn. Pharmacol Rev. 2012;64:540–82.

    Article  CAS  Google Scholar 

  27. Hsieh YT, Liu NM, Ohmori E, Yokota T, Kajimura I, Akaike T, et al. Transcription profiles of the ductus arteriosus in Brown-Norway rats with irregular elastic fiber formation. Circ J: Off J Jpn Circ Soc. 2014;78:1224–33.

    Article  Google Scholar 

  28. Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation. 2005;112:2477–86.

    Article  CAS  Google Scholar 

  29. Kandasamy Y, Hartley L, Rudd D, Smith R. The association between systemic vascular endothelial growth factor and retinopathy of prematurity in premature infants: a systematic review. Br J Ophthalmol. 2017;101:21–24.

    Article  Google Scholar 

  30. Waleh N, Seidner S, McCurnin D, Giavedoni L, Hodara V, Goelz S, et al. Anatomic closure of the premature patent ductus arteriosus: The role of CD14+/CD163+mononuclear cells and VEGF in neointimal mound formation. Pediatr Res. 2011;70:332–8.

    Article  CAS  Google Scholar 

  31. Iivanainen E, Paatero I, Heikkinen SM, Junttila TT, Cao R, Klint P, et al. Intra- and extracellular signaling by endothelial neuregulin-1. Exp Cell Res. 2007;313:2896–909.

    Article  CAS  Google Scholar 

  32. Clement CM, Thomas LK, Mou Y, Croslan DR, Gibbons GH, Ford BD. Neuregulin-1 attenuates neointimal formation following vascular injury and inhibits the proliferation of vascular smooth muscle cells. J Vasc Res. 2007;44:303–12.

    Article  CAS  Google Scholar 

  33. Capece A, Vasieva O, Meher S, Alfirevic Z, Alfirevic A. Pathway analysis of genetic factors associated with spontaneous preterm birth and pre-labor preterm rupture of membranes. PLoS ONE. 2014;9:e108578.

    Article  Google Scholar 

  34. Nupponen I, Kuuliala A, Siitonen S, Repo H, Kuuliala K. Cord blood monocytes, neutrophils and lymphocytes from preterm and full-term neonates show multiple aberrations in signalling profiles measured using phospho-specific whole-blood flow cytometry. Scand J Immunol. 2013;78:426–38.

    Article  CAS  Google Scholar 

  35. Inayat M, Bany-Mohammed F, Valencia A, Tay C, Jacinto J, Aranda JV, et al. Antioxidants and biomarkers of oxidative stress in preterm infants with symptomatic patent ductus arteriosus. Am J Perinatol. 2015;32:895–904.

    Article  Google Scholar 

  36. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.

    Article  CAS  Google Scholar 

  37. Bixler GM, Powers GC, Clark RH, Walker MW, Tolia VN. Changes in the diagnosis and management of patent ductus arteriosus from 2006 to 2015 in United States neonatal intensive care units. J Pediatr. 2017;189:105–12.

    Article  Google Scholar 

  38. Matejcic M, Saunders EJ, Dadaev T, Brook MN, Wang K, Sheng X, et al. Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nat Commun. 2018;9:4616.

    Article  Google Scholar 

  39. Ahmad A, Sundquist K, Palmer K, Svensson PJ, Sundquist J, Memon AA. Risk prediction of recurrent venous thromboembolism: a multiple genetic risk model. J Thromb Thrombolysis. 2018. https://doi.org/10.1007/s11239-018-1762-7

  40. Jansen PR, Petrus NCM, Venema A, Posthuma D, Mannens M, Sprikkelman AB, et al. Higher polygenetic predisposition for asthma in cow’s milk allergic children. Nutrients 2018;10:1582.

  41. Zheng SL, Sun J, Wiklund F, Smith S, Stattin P, Li G, et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008;358:910–9.

    Article  CAS  Google Scholar 

  42. Xiao X, Hao J, Wen Y, Wang W, Guo X, Zhang F. Genome-wide association studies and gene expression profiles of rheumatoid arthritis: an analysis. Bone & Jt Res. 2016;5:314–9.

    Article  CAS  Google Scholar 

  43. Go MJ, Lee Y, Park S, Kwak SH, Kim BJ, Lee J. Genetic-risk assessment of GWAS-derived susceptibility loci for type 2 diabetes in a 10 year follow-up of a population-based cohort study. J Hum Genet. 2016;61:1009–12.

    Article  CAS  Google Scholar 

  44. Hallberg P, Eriksson N, Ibanez L, Bondon-Guitton E, Kreutz R, Carvajal A, et al. Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population. Lancet Diabetes & Endocrinol. 2016;4:507–16.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, 5U10 HD040492-12; RO1HL109199 NIH (JD); 6-FY11-261 and 21-FY13-19 March of Dimes (JM) and individual grant numbers from sites within the NRN are included below.

The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (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 Neonatal Research Network’s Glutamine trial which included the Genomic Study through cooperative agreements. While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data collected at participating NRN sites were transmitted to RTI International, the data coordinating center (DCC) for the NRN, which stored, managed, and analyzed the data for this study. On behalf of the network, Drs. Abhik Das (DCC PI) and Grier Page (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:

NRN Genomics Subcommittee: C. Michael Cotten, MD MHS (chair); Jeff Murray, MD (vice chair); Namasivayam Ambalavanan, MD; Edward F. Bell, MD; Kurt Schibler, MD; Beena G. Sood, MD; David K. Stevenson, MD; Barbara J. Stoll, MD; Krisa P. Van Meurs, MD; Waldemar A. Carlo MD; Seetha Shankaran MD; Ronald N. Goldberg, MD; Richard A. Ehrenkranz, MD; Jon E. Tyson, MD, MPH; Ivan D. Frantz III, MD; Abhik Das; Rosemary D. Higgins, MD; Karen J. Johnson, RN BSN.

NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati.

Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Abbot R. Laptook, MD; William Oh, MD; Lewis P. Rubin, MD; Angelita M. Hensman, RN BSN.

Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Avroy A. Fanaroff, MD; Michele C. Walsh, MD MS; Nancy S. Newman, RN; Bonnie S. Siner, RN.

Cincinnati Children’s Hospital Medical Center, University Hospital and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – Edward F. Donovan, MD; Vivek Narendran, MD MRCP; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Jody Hessling, RN; Marcia Worley Mersmann, RN CCRC; Holly L. Mincey, RN BSN.

Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (M01 RR30, U10 HD40492) – Kathy J. Auten, MSHS.

Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (U10 HD27851, M01 RR39) – Ellen C. Hale, RN BS CCRC.

Eunice Kennedy Shriver National Institute of Child Health and Human Development – Linda L. Wright, MD; Sumner J. Yaffe, MD; Elizabeth M. McClure, MEd.

Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750) – Brenda B. Poindexter, MD MS; James A. Lemons, MD; Diana D. Appel, RN BSN; Dianne E. Herron, RN; Leslie D. Wilson, BSN CCRC.

RTI International (U10 HD36790) – W. Kenneth Poole, PhD (deceased); Scott A. McDonald, BS; Betty K. Hastings; Kristin M. Zaterka-Baxter, RN BSN; Jeanette O’Donnell Auman, BS; Scott E. Schaefer, MS.

Stanford University, Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70) – David K. Stevenson, MD; Krisa P. Van Meurs, MD; M. Bethany Ball, BS CCRC.

University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN.

University of California – San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461) – Neil N. Finer, MD; Maynard R. Rasmussen, MD; David Kaegi, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Wade Rich, BSHS RRT.

University of Iowa Stead Family Children’s Hospital (U10 HD53109, M01 RR59, UL1 TR442) – Edward F. Bell, MD; Karen J. Johnson, RN.

University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587) – Charles R. Bauer, MD; Shahnaz Duara, MD; Ruth Everett-Thomas, RN MSN.

University of New Mexico Health Sciences Center (U10 HD27881, M01 RR997) – Lu-Ann Papile, MD; Conra Backstrom Lacy, RN.

University of Tennessee (U10 HD21415) – Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN BSN.

University of Texas Southwestern Medical Center at Dallas Parkland Health & Hospital System and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Abbot R. Laptook, MD; Walid A. Salhab, MD; Susie Madison, RN.

University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon B. Johnson General Hospital (U10 HD21373) – Kathleen A. Kennedy, MD MPH; Brenda H. Morris, MD; Esther G. Akpa, RN BSN; Patty A. Cluff, RN; Claudia I. Franco, RNC MSN; Anna E. Lis, RN BSN; Georgia E. McDavid, RN; Patti Pierce Tate, RCP.

Wake Forest University Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122) – T. Michael O’Shea, MD MPH; Nancy J. Peters, RN CCRP.

Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385) – G. Ganesh Konduri, MD; Rebecca Bara, RN BSN; Geraldine Muran, RN BSN.

Yale University, Yale-New Haven Children’s Hospital (U10 HD27871, M01 RR6022) – Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    John M. Dagle, Kelli K. Ryckman, Allison M. Momany, Edward F. Bell & Jeffrey C. Murray

  2. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Cassandra N. Spracklen

  3. Department of Pediatrics, Duke University, Durham, NC, USA

    C. Michael Cotten & Ronald N. Goldberg

  4. Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Durham, NC, USA

    Joshua Levy

  5. Social, Statistical and Environmental Sciences Unit, RTI International, Atlanta, GA, USA

    Grier P. Page

  6. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Waldemar A. Carlo

  7. Department of Pediatrics, Wayne State University, Detroit, MI, USA

    Seetha Shankaran

  8. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

    Richard A. Ehrenkranz

  9. Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA

    Jon E. Tyson

  10. Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Barbara J. Stoll

Authors
  1. John M. Dagle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kelli K. Ryckman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cassandra N. Spracklen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Allison M. Momany
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Michael Cotten
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joshua Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Grier P. Page
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edward F. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Waldemar A. Carlo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seetha Shankaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ronald N. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Richard A. Ehrenkranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jon E. Tyson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Barbara J. Stoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jeffrey C. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

Corresponding author

Correspondence to John M. Dagle.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dagle, J.M., Ryckman, K.K., Spracklen, C.N. et al. Genetic variants associated with patent ductus arteriosus in extremely preterm infants. J Perinatol 39, 401–408 (2019). https://doi.org/10.1038/s41372-018-0285-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-018-0285-6

Search

Advanced search

Quick links