4.15 EPIGENETIC AND GENETIC VARIANTS IN THE HTR1B GENE AND CLINICAL IMPROVEMENT IN CHILDREN AND ADOLESCENTS TREATED WITH FLUOXETINE

Objectives: The objectives of this presentation are to evaluate the influence of genetic variants specifically located in transcription factor binding sites (TFBSs) on clinical improvement in children and adolescents treated with fluoxetine and to assess whether methylation levels at the HTR1B promoter region could be associated with pharmacological response. Methods: A total of 83 children and adolescents diagnosed with MDD, OCD, or generalized anxiety disorder were recruited. They were assessed clinically with several scales, 12 weeks after initiating an antidepressant treatment with fluoxetine for the first time. We selected HTR1B single nucleotide polymorphisms (SNPs) with minor allele frequency higher than 10 percent specifically located in the TFBS, which could therefore be responsible for an altered HTR1B gene expression. Moreover, we analyzed methylation levels of a relevant CpG island in the HTR1B promoter region. Results: Two SNPs, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous patients for the rs9361233 showed higher scores on the Clinical Global Impressions- Improvement (CGI-I) scale (P = 0.0018). In addition, heterozygous patients for the rs9361235 showed higher scores on the CGI-I scale (P = 0.0016), as well as lower score reductions on the Obsessive-Compulsive Inventory-Child Version (OCI-CV) scale (P = 0.00059). The heterozygous genotype combination analysis, including these two SNPs and another functional one (rs130058), which was also located in a TFBS showed a negative correlation with clinical improvement. Compared with patients that were homozygous for the three SNPs (N = 39), lower clinical improvement was found in patients who were heterozygous for at least one of them (N = 25). The lowest improvement was shown by patients who were heterozygous for the three SNPs (N = 19). Regressions were significant for the majority of the clinical scales assessed: OCI-CV (P = 0.00007); Screen for Child Anxiety Related Disorders (P = 0.0013); Global Assessment of Functioning/ Children's Global Assessment Scale (P = 0.004); CGI-S (P = 0.004); and CGI-I (P = 0.00002). Methylation in the HTR1B promoter region ranged from 28 percent (CpG1) to 43 percent (CpG5). Average methylation level of the seven CpGs analyzed was highly correlated with each individual CpG (r > 0.7; P < 0.0001). Conclusions: These results give more evidence for the role of epigenetic and genetic fact