Apolipoprotein E gene polymorphisms: a risk factor for preterm brain injury?

Abstract

Although a decrease in the incidence of intraventricular haemorrhage (IVH) in infants born preterm has been observed, it remains a common and serious complication of preterm birth, particularly in infants born extremely preterm. It is well known that high-grade IVH (with involvement of periventricular brain tissue) is associated with a significant risk for neuromotor and developmental impairment. Factors relating to blood flow and angiogenesis contribute to IVH, and various environmental risk factors have been described. These include pregnancy complications (inflammation), gestational age at birth, sex, need of cardiopulmonary resuscitation after delivery, early onset sepsis, and respiratory complications, among others. More recently, there has been a growing body of work on genetics and gene-environment interactions in neonatal disorders. For IVH, gene variants related to inflammation, vascular and coagulation pathways, as well as angiogenesis have been examined as candidate genes that pose an increased risk for IVH. But results have been difficult to replicate and, indeed, overall findings have so far been disappointing. The study by Dzietko et al. uses material collected from 53 neonatal units in Germany to investigate associations between apolipoprotein E (APOE) genotype polymorphism and severe IVH in infants born preterm (between 22–32wks’ gestation), controlling for some relevant environmental perinatal and demographic factors in their analyses. APOE is an interesting potential candidate gene in the context of preterm IVH. In the typically developing human brain, apolipoprotein E is found in glia and neurons. APOE polymorphisms have been associated with several disorders, and, although pathomechanisms are not yet clear, it has been proposed that APOE4 genotype – broadly speaking – impairs the brain’s ability for repair and regeneration. The APOE4 genotype has long been associated with sporadic and familial Alzheimer disease, more recently with cerebral non-haemorrhagic amyloid angiopathy haemorrhage (CAA), and also poorer recovery after traumatic brain injury, and intracerebral haemorrhage; APOE2 genotype appears to be protective against brain atrophy in ageing, but has also been associated with haemorrhagic CAA. Dzietko et al. could now show that specific APOE genotypes, APOE4 and APOE2, were associated with severe IVH in very and extremely preterm birth. The study by Dzietko et al. adds interesting new information on potential risk factors for severe IVH in infants born preterm and raises the question of whether APOE genotype should be included into a ‘risk evaluation metric’ of genetic and environmental factors for this common complication of preterm birth. It also hints at APOE genotypes possibly playing a role in other neurovascular disorders that we observe at relatively early stages of brain development. However, since the majority of preterm IVH occurs in the first 2 to 3 days after birth, it appears doubtful that APOE genotyping will have implications for tailored neonatal care or neuroprotective treatment unless the genotype is determined antenatally or available immediately after delivery. However, APOE genotyping might be a very useful tool to identify those infants born preterm, within the group of those who have suffered IVH, at either high or low risk for neurodevelopmental sequela. This would allow stratification for intensity of follow-up and individually tailored early intervention. For this, information on whether and how long-term outcomes after IVH differ between genotypes is needed. Large, well-characterized cohorts (such as in Dzietko et al.) who are then prospectively followed up with standardized protocols are ideally suited to address these further questions. It will be interesting to see such data hopefully emerging in the coming years. For now, prevention of preterm birth and further optimization of delivery room and neonatal care remains the primary strategy for prevention of IVH in infants born very and extremely preterm.