Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age

Cecil M. Y. Chau, Manon Ranger, Dian Sulistyoningrum, Angela M. Devlin, Tim F. Oberlander, Ruth E. Grunau

Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behavior problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype) (p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children at 7 years (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population.