Abstract
Background
Twin studies suggest that genetic factors may account for up to 50% increased risk for necrotizing enterocolitis (NEC), but genome-wide association studies for NEC are lacking.
Methods
Genotyping was done on Illumina BeadChip, followed by analysis using PLINK with logistic regression under an additive model.
Results
Among 751 extremely-low-birth-weight (<1,000 g, >401 g) neonates, 30 had surgical NEC. Two hundred and sixty-one single-nucleotide polymorphisms (SNPs) showed association with NEC at P<0.05, of which 35 were significant at P<10−7. Minor allele(s) in a cluster of SNPs spanning a 43-kb region of chromosome 8 (8q23.3) conferred an odds ratio of 4.72 (95% confidence interval (CI): 2.51–8.88) for elevated risk of NEC. Two smaller clusters on chromosome 14 and chromosome 11 exhibited P values of 10–7–10–8. The chromosome 8 cluster is in an intergenic region between CUB and Sushi multiple domains 3 (−1.43 Mb) and trichorhinophalangeal syndrome I (+542 kb). RNA sequencing in this region identified a potential novel open-reading frame corresponding to a long interspersed element-1 retrotransposable element.
Conclusion
Genetic variation in an intergenic region of chromosome 8 is associated with increased risk for NEC with a mechanism that is yet to be identified.
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Acknowledgements
We are indebted to our medical and nursing colleagues, and the infants and their parents who agreed to take part in this study. 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, Abhik Das (DCC PI) and Grier Page (DCC statistician) had full access to all the data in the study and took responsibility for the integrity of the data and accuracy of the data analysis.
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The authors have no financial relationships relevant to this article to disclose, and the study sponsors have not been involved in any of the following: (1) study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication.
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STATEMENT OF FINANCIAL SUPPORT:
The National Institutes of Health (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, and UL1 RR24979) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (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 U10 HD53109) provided grant support for the Neonatal Research Network’s Genomics Study.
The funding agencies provided overall oversight for study conduct, but all data analyses and interpretation were independent of the funding agencies. Although NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD.
Members of the Genomics Subcommittee of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICD) Neonatal Research Network
C. Michael Cotten6; Grier Page7; Waldemar A. Carlo8; Edward F. Bell9; Ronald N. Goldberg6; Kurt Schibler10; Rosemary D. Higgins11; Beena G. Sood12; David K. Stevenson13; Barbara J. Stoll14; Krisa P. Van Meurs12; Karen J. Johnson9; Abhik Das15; Scott A. McDonald7; Kristin M. Zaterka-Baxter7; Kathleen A. Kennedy16; Pablo J. Sánchez17; Shahnaz Duara18; Michele C. Walsh19; Seetha Shankaran20; Sheldon B. Korones21; Neil N. Finer22; effrey C. Murray9 for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
6Department of Pediatrics, Duke University, Durham, NC; 7Social, Statistical, and Environmental Sciences, RTI International, Research Triangle Park, NC; 8Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; 9University of Iowa, Department of Pediatrics, Iowa City, IA; 10Department of Pediatrics, University of Cincinnati, Cincinnati, OH; 11Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; 12Department of Pediatrics, Wayne State University, Detroit, MI; 13Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, CA; 14Emory University School of Medicine, Department of Pediatrics, Children’s Healthcare of Atlanta, Atlanta, GA; 15Social, Statistical, and Environmental Sciences, RTI International, Rockville, MD; 16Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX; 17Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; 18University of Miami Miller School of Medicine, Miami, FL; 19Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, OH; 20Department of Pediatrics, Wayne State University, Detroit, MI; 21Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN; 22University of California at San Diego, San Diego, CA.
The following investigators participated in this study:
NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati.
Case Western Reserve University, Rainbow Babies and Children’s Hospital (U10 HD21364, M01 RR80)—Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Michele C. Walsh, MD MS; Nancy S. Newman, RN; Bonnie S. Siner, RN.
Cincinnati Children’s Hospital Medical Center, and University Hospital (U10 HD27853, M01 RR8084)—Kurt Schibler, MD; 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)—Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Kathy J. Auten, MSHS.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (U10 HD27851, M01 RR39)—Barbara J. Stoll, MD; Ellen C. Hale, RN BS CCRC.
Eunice Kennedy Shriver National Institute of Child Health and Human Development—Rosemary D. Higgins, MD; Linda L. Wright, MD; Sumner J. Yaffe, MD; Elizabeth M. McClure, Med; Stephanie Wilson Archer, MA.
RTI International (U10 HD36790)—Abhik Das, PhD; W. Kenneth Poole, PhD; Grier Page, PhD; Scott A. McDonald, BS; Betty K. Hastings; Jeanette O’Donnell Auman, BS; Kristin M. Zaterka-Baxter, RN BSN.
Stanford University, Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70)—Krisa P. Van Meurs, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32)—Waldemar A. Carlo MD; 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 Children’s Hospital and Mercy Medical Center (U10 HD53109, M01 RR59, UL1 TR442)—Edward F. Bell, MD; Jeffrey C. Murray, MD; Karen J. Johnson, RN.
University of Miami Holtz Children’s Hospital (U10 HD21397, M01 RR16587)—Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN.
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 and Hospital System, and Children’s Medical Center of Dallas (U10 HD40689, M01 RR633)—Pablo J. Sánchez, MD; Abbot R. Laptook, MD; Walid A. Salhab, MD; Susie Madison, RN; Nancy A. Miller, RN; Gaynelle Hensley, RN; Alicia Guzman.
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; Jon E. Tyson, MD MPH; Kathleen A. Kennedy, MD MPH; 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.
Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385)—Seetha Shankaran, MD; Beena G. Sood, MD MS; G. Ganesh Konduri, MD; Rebecca Bara, RN BSN; Geraldine Muran, RN BSN.
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Jilling, T., Ambalavanan, N., Cotten, C. et al. Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8. Pediatr Res 83, 943–953 (2018). https://doi.org/10.1038/pr.2018.33
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DOI: https://doi.org/10.1038/pr.2018.33
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