Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Chau CM

PROVIDER: S-EPMC4251438 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Chau Cecil M Y CM Ranger Manon M Sulistyoningrum Dian D Devlin Angela M AM Oberlander Tim F TF Grunau Ruth E RE

Frontiers in behavioral neuroscience 20141202

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) ...[more]

PMID: 25520635

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Project description:A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.

Project description:IntroductionThe mouse placenta accumulates and possibly produces serotonin (5-hydroxytryptamine; 5-HT) in parietal trophoblast giant cells (pTGC) located at the interface between the placenta and maternal deciduum. However, the roles of 5-HT in placental function are unclear. This lack of information is unfortunate, given that selective serotonin-reuptake inhibitors are commonly used to combat depression in pregnant women. The high affinity 5-HT transporter SLC6A4 (also known as SERT) is the target of such drugs and likely controls much of 5-HT uptake into pTGC and other placental cells. We hypothesized that ablation of the Slc6a4 gene would result in morphological changes correlated with placental gene expression changes, especially for those involved in nutrient acquisition and metabolism, and thereby, provide insights into 5-HT placental function.MethodsPlacentas were collected at embryonic age (E) 12.5 from Slc6a4 knockout (KO) and wild-type (WT) conceptuses. Histological analyses, RNAseq, qPCR, and integrative correlation analyses were performed.ResultsSlc6a4 KO placentas had a considerable increased pTGC to spongiotrophoblast area ratio relative to WT placentas and significantly elevated expression of genes associated with intestinal functions, including nutrient sensing, uptake, and catabolism, and blood clotting. Integrative correlation analyses revealed upregulation of many of these genes was correlated with pTGC layer expansion. One other key gene was dopa decarboxylase (Ddc), which catalyzes conversion of L-5-hydroxytryptophan to 5-HT.DiscussionOur studies possibly suggest a new paradigm relating to how 5-HT operates in the placenta, namely as a factor regulating metabolic functions and blood coagulation. We further suggest that pTGC might be functional analogs of enterochromaffin 5-HT-positive cells of the intestinal mucosa, which regulate similar activities within the gut. Further work, including proteomics and metabolomic studies, are needed to buttress our hypothesis.

Dataset Information

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

Publications

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

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