Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy

Author:

Montaldo Paolo12,Burgod Constance1,Herberg Jethro A.3,Kaforou Myrsini3,Cunnington Aubrey J.3,Mejias Asuncion45,Cirillo Grazia2,Miraglia Del Giudice Emanuele2,Capristo Carlo2,Bandiya Prathik6,Kamalaratnam Chinnathambi N.7,Chandramohan Rema7,Manerkar Swati8,Rodrigo Ranmali9,Sumanasena Samanmali9,Krishnan Vaisakh1,Pant Stuti1,Shankaran Seetha10,Thayyil Sudhin1

Affiliation:

1. Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom

2. Department of Women's and Children's Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy

3. Section of Paediatric Infectious Disease and Centre for Paediatrics and Child Health, Department of Infectious Disease, Imperial College London, London, United Kingdom

4. Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, Tennessee

5. Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio

6. Department of Neonatology, Indira Gandhi Institute of Child Health, Bengaluru, India

7. Institute of Child Health, Department of Neonatology, Madras Medical College, Chennai, India

8. Department of Neonatology, Lokmanya Tilak Municipal Medical College, Mumbai, India

9. Department of Pediatrics, University of Kelaniya, Colombo, Sri Lanka

10. Neonatal-Perinatal Medicine, Wayne State University, Detroit, Michigan

Abstract

ImportanceInduced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden.ObjectiveTo investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia.Design, Setting, and ParticipantsThis case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023.ExposureWhole-blood RNA that underwent next-generation sequencing.Main Outcome and MeasuresThe primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort.ResultsThe HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = −4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14).Conclusions and RelevanceThis case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Publisher

American Medical Association (AMA)

Cited by 6 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Stay cool and keep moving forwards;Pediatric Research;2024-09-06

2. Pipeline to Neonatal Clinical Transformation;Clinics in Perinatology;2024-09

3. Moving the Needle in Low-Resource Settings;Clinics in Perinatology;2024-09

4. How do we reach the goal of personalized medicine for neuroprotection in neonatal hypoxic-ischemic encephalopathy?;Seminars in Perinatology;2024-08

5. Le neurodéveloppement et la neuroprotection du jeune enfant;Gynécologie Obstétrique Fertilité & Sénologie ;2024-07

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