Gene–Environment Interactions in Severe Intraventricular Hemorrhage of Preterm Neonates

nature publishing group Review Gene–environment interactions in severe intraventricular hemorrhage of preterm neonates Laura R. Ment1,2, Ulrika Ådén3, Aiping Lin1, Soo Hyun Kwon1, Murim Choi4, Mikko Hallman5, Richard P. Lifton4, Heping Zhang6 and Charles R. Bauer7; for the Gene Targets for IVH Study Group Intraventricular hemorrhage (IVH) of the preterm neonate is of surviving neonates develop cognitive disability and/or a complex developmental disorder, with contributions from cerebral palsy (2,3). In addition, 20% of nondisabled survi- both the environment and the genome. IVH, or hemorrhage vors suffer executive function and neuropsychiatric disorders, into the germinal matrix of the developing brain with second- confirming that severe IVH is a major pediatric public health ary periventricular infarction, occurs in that critical period of problem (4,5). time before the 32nd to 33rd wk postconception and has been Multiple lines of clinical data support the hypothesis that, attributed to changes in cerebral blood flow to the immature similar to other preterm morbidities (6,7), the etiology of IVH germinal matrix microvasculature. Emerging data suggest that is multifactorial. First, despite the development of sophisticated genes subserving coagulation, inflammatory, and vascular neonatal intensive care strategies, IVH remains a significant pathways and their interactions with environmental triggers problem of prematurity. Maternal transport, antenatal steroid may influence both the incidence and severity of cerebral administration, and improved resuscitation techniques have injury and are the subject of this review. Polymorphisms in the become standard of care in neonatal tertiary care units world- Factor V Leiden gene are associated with the atypical timing of wide (8–11), but the incidence of severe IVH has remained IVH, suggesting an as yet unknown environmental trigger. The 13–15% for almost 20 y (8,12). methylenetetrahydrofolate reductase (MTHFR) variants render Although the incidence of IVH is inversely related to ges- neonates more vulnerable to cerebral injury in the presence tational age (GA) at birth, the risk period for hemorrhage is of perinatal hypoxia. The present study demonstrates that independent of GA (13,14). The incidence of severe IVH is 7% the MTHFR 677C>T polymorphism and low 5-min Apgar score for those born at 28 wk and 26% for neonates born 4 wk ear- additively increase the risk of IVH. Finally, review of published lier, but the critical period for hemorrhage is the first 4–5 d preclinical data suggests the stressors of delivery result in hem- of life for both the groups. These data suggest that either the orrhage in the presence of mutations in collagen 4A1, a major transition to extrauterine life and/or the triggers to which the structural protein of the developing cerebral vasculature. neonates are exposed contribute to hemorrhage, and both Maternal genetics and fetal environment may also play a role. hypoxemia and inflammation have been implicated in severe IVH of the prematurely born. onverging data suggest that intraventricular hemorrhage Furthermore, both gender and twin studies support the C(IVH) of the preterm neonate is a complex developmental hypothesis that IVH is a complex disorder. Preterm males disorder, with contributions from both the environment and are more likely than females to experience severe IVH (15). the genome of the child. IVH, or hemorrhage into the ger- Similarly, studying 450 twin pairs, Bhandari et al. (16) reported minal matrix (GM) of the developing brain with secondary that 41.3% of the variance in IVH risk is attributable to familial periventricular infarction as shown in Figure 1, occurs in that and environmental factors. Candidate gene studies implicate the critical period of time before the 32nd to 33rd wk postconcep- inflammatory, coagulation, and vascular pathways, and recent tion and has been attributed to changes in cerebral blood flow data suggest that time of hemorrhage may play a role (17–19). (CBF) to the immature GM microvasculature. Inflammation, The purpose of this review is to examine preclinical and clin- coagulation, and vascular factors may also play a role. The ical data supporting the hypothesis that severe IVH is attrib- more severe grades are characterized by acute distension of utable in part to the interaction of the environment with the the cerebral ventricular system with blood (grade 3) and IVH neonatal genome. Based on the pathogenesis of hemorrhage, with parenchymal venous infarction (grade 4) (1). Mortality is factors mediating coagulation, inflammation, and vascular high in infants with severe IVH, and one-quarter to one-half pathways have been chosen for review. 1Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut; 2Department of Neurology, Yale University School of Medicine, New Haven, Connecticut; 3Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden; 4Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; 5Department of Pediatrics and Adolescence, Oulu University Hospital, University of Oulu, Oulu, Finland; 6Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; 7Department of Pediatrics, University of Miami Leonard M. Miller School of Medicine, Miami, Florida. Correspondence: Laura R. Ment ([email protected]) Received 11 April 2013; accepted 6 August 2013; advance online publication 11 December 2013. doi:10.1038/pr.2013.195 Copyright © 2014 International Pediatric Research Foundation, Inc. Volume 75 | Number 1 | January 2014 Pediatric ReSearch 241 Review Ment et al. abstimuli ranging from protein-calorie dietary restriction to hypoxia and fetal inflammatory exposures. Offspring of women experiencing preeclampsia, a putative marker for fetal hypoxia, have both hypertension and endothelial dysfunction during young adulthood (23). Similarly, in preclinical mod- 25.54 mm els, offspring of mothers exposed to protein-calorie depriva- tion during pregnancy also have vascular dysfunction, and these findings are reversed by maternal folate supplementa- tion (24). Of note, folate deficiencies have also been associated with abnormalities in DNA methylation (25). Also, in preclinical studies, the endothelium-dependent abnormalities in the Figure 1. Severe intraventricular hemorrhage (IVH). Coronal ultrasounds offspring of restricted diet pregnancies are ameliorated by the at postnatal age (a) 1 d and (b) 4 d from a 28-wk gestation neonate with administration of histone deacetylase inhibitors, suggesting a IVH. In a, blood is seen in the germinal matrix and filling the right lateral transgenerational etiology for the findings (26). ventricle; at postnatal d 4, the ventricular system is dilated, and blood is Finally, the interactions between genetic polymorphisms, seen both filling and distending the right lateral ventricle as well as in the parenchyma of the right hemisphere, consistent with grade 4 IVH. epigenetic mechanisms such as DNA methylation, and expression are complex. Emerging data suggest, however, that genetic MODELS FOR INTERACTION BETWEEN THE ENVIRONMENT variants regulate methylation, and methylation regulates gene AND THE GENOME expression. Thus, a genetic variant that creates or negates a Although several investigators have hypothesized that IVH DNA C-phosphate-G methylation site in the promoter region is secondary to the interaction of the environment and the of a gene may significantly impact expression of that gene (27). genome (20), the mechanisms by which genetic predisposition and environmental exposures interact are just beginning to be PATHWAYS FOR ALTERATION OF THE IVH EPIGENOME described. Review of published literature interrogating vascu- Studies investigating mechanisms by which fetal or preterm lar and environmental interactions suggest at least two differ- exposures may alter the epigenome to promote or prevent ent mechanisms. These include the impact of an environmental IVH include the effects of hypoxia, inflammation, nutrition, perturbation on a system harboring a known polymorphism, and oxidative stress. while the other stems from research addressing the influence IVH has long been associated with hypoxic ischemic events, of fetal programming on adult disorders postulating the role of and putative inflammatory, excitotoxic, and apoptotic path- epigenetics. Underlying both proposed mechanisms is the ways are involved in the complex cascade following neonatal recognition that IVH is a developmental disorder occurring hypoxia ischemia. The hypoxia-inducible transcription fac- within a critical period of time, and both the polymorphisms tors (HIFs) are among the endogenous adaptive mechanisms and environment events we describe may result in very dif- modifying this cascade of events. HIFs are heterodimers of ferent or even unremarkable phenotypes in the term infant or HIF-α and HIF-β subunits that belong to a family of basic older child. helix-loop-helix transcription factors. HIF-1 and HIF-2 are In the first model, a gene confers vulnerability to environ- important regulators of oxygen-dependent gene transcription mental triggers (21). A common example is hypercarbia. that modulate oxygen and metabolic supply during hypoxia. Hypercarbia occurs in association with apneic events, lung HIF target genes include those with vasoactive and vasopro- disease, pneumothoraces, pulmonary hemorrhage, and other liferative effects including vascular endothelial growth

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