T细胞失调与早产儿脑病相关：medRxiv临床预印本

Abstract

Preterm birth is strongly linked to systemic inflammation and encephalopathy of prematurity, which underlies subsequent cognitive impairment. T-cell immunity contributes to brain-immune crosstalk across the life course but its role in the pathogenesis of encephalopathy of prematurity is unknown. Protein epigenetic scores are DNA methylation (DNAm)-based proxies of circulating proteins. We tested the hypothesis that T-cell dysregulation has a specific role in child neurodevelopment following preterm birth. Multimodal data were collected from 144 preterm infants (median gestational age at birth 29+5 weeks [range 23+3 to 32+6]) recruited to a prospective cohort study: saliva DNAm for protein epigenetic score derivation and brain MRI, both at term-equivalent age, and the Mullen Scales of Early Learning Composite score at 5 years from a subset. We investigated associations of the epigenetic scores for cytotoxic and regulatory T cell-associated molecule (DNAm CRTAM) and C-reactive protein (DNAm CRP; a non-specific marker of inflammation) with MRI metrics of encephalopathy of prematurity: global and regional brain volumes, and general factors of diffusion tensor imaging and neurite orientation dispersion and density imaging metrics averaged across 42 white matter tracts. We tested whether DNAm CRTAM explains more variance than DNAm CRP in MRI metrics of the encephalopathy of prematurity and cognitive scores in childhood. Higher neonatal DNAm CRTAM was associated with lower general factor of fractional anisotropy (β = -0.252, q = 0.011) and higher general factors of radial diffusivity (β = 0.215, q = 0.039), mean diffusivity (β = 0.198, q = 0.047) and orientation dispersion index (β = 0.201, q = 0.048), independent of inflammatory morbidities and other biological covariates after false discovery rate correction. DNAm CRTAM explained more variance than DNAm CRP (maximum incremental R² = 4.2% vs 1.5%) in diffusion MRI metrics. Higher neonatal DNAm CRTAM was associated with lower cognitive scores at 5 years, independent of DNAm CRP and other covariates (β = -0.332, P = 0.008), and explained more variance in cognitive scores than DNAm CRP (incremental R² = 9.4% vs 1.2%). An epigenetic proxy of CRTAM in preterm infants is associated with both encephalopathy of prematurity in the neonatal period and lower cognitive performance at 5 years, explaining greater incremental variance than a non-specific marker of inflammation. The data implicate T-cell dysregulation in the pathophysiology of atypical neurodevelopment following preterm birth.

Competing Interest Statement

LM has received speaker and consultancy fees from Illumina. REM is a scientific advisor to the Epigenetic Clock Development Foundation and to Optima partners. All other authors declare that they have no competing interests.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UK National Research Ethics Service, South East Scotland Research Ethics Committee (11/55/0061, 13/SS/0143) and NHS Lothian Research and Development (16/SS/0154) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Anonymised data included in these analyses are deposited in Edinburgh DataVault (https://doi.org/10.7488/e65499db-2263-4d3c-9335-55ae6d49af2b) and are available to researchers under the terms of the Theirworld Edinburgh Birth Cohort Data Access and Collaboration policy available at https://reproductive-health.ed.ac.uk/theirworld-edinburgh-birth-cohort-tebc/for-researchers/data-access-and-collaboration. The data are not part of an open repository due to the terms of the informed parent/guardian consent, which stipulates that the use of anonymised data is for studies of perinatal health that have been approved by regulatory bodies.

https://doi.org/10.7488/e65499db-2263-4d3c-9335-55ae6d49af2b

Funder Information Declared

Wellcome Trust, https://ror.org/029chgv08, 218493/Z/19/Z, 221890/Z/20/Z

Theirworld

Medical Research Council, https://ror.org/03x94j517, MR/X003434/1, UKRI3688

Biotechnology and Biological Sciences Research Council, UKRI/BB/C001941/1