title: Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates.
abstract: Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.
authors.affiliation: 1] Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut [2] Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Ment
authors.affiliation: Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Adén
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Pediatrics and Adolescence, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001034:Apgar Score; D001777:Blood Coagulation / Q000235:genetics; D002552:Cerebral Ventricles / Q000098:blood supply*; D002560:Cerebrovascular Circulation; D024141:Collagen Type IV / Q000235:genetics; D005165:Factor V / Q000235:genetics; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005865:Gestational Age; D006801:Humans; D002534:Hypoxia, Brain / Q000150:complications; D007223:Infant; D007234:Infant, Premature; D018836:Inflammation Mediators; D020300:Intracranial Hemorrhages / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D010641:Phenotype; D047928:Premature Birth; D011379:Prognosis; D012307:Risk Factors
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV; D018836:Inflammation Mediators; C095381:factor V Leiden; D005165:Factor V; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)