Effect of phospholipase C enzyme gene and environmental factors on antidepressant treatment in Han Chinese population

Abstract

Background: The efficacy of antidepressant could be influenced by various factors including the genetic factors, negative life events and adverse childhood experiences. It has been recently suggested that antidepressant could modulate the function of the phospholipase C (PLC) and further regulate the activation of phosphoinositide (PI). PLCE1, an important enzymes of PLC families, catalyzes the hydrolysis of phosphatidylinositol bisphosphate (PIP2) to generate second messengers, such as IP3 and DAG. On the other side, PLCE1 could participated mitogen activated protein kinase (MAPK) pathway, the possible target of the antidepressant, via stimulating extracellular signal regulated kinase (ERK) activation. The aim of this study was to examine the associations of antidepressant efficacy with PLCE1 gene and the role of interactions between PLCe gene variants and stress factors on antidepressant efficacy. Methods: A total of 277 patients with depression met with DSM-? and CCMD-3 diagnosis criteria were recruited and were assessed with 17-item Hamilton Depression Rating Scale (HAMD-17) before and after 8-week antidepressants treatment. Clinical response was considered when a decrease of at least 50% in the baseline HDRS scores after 8 weeks antidepressant treatment. The remission criterion was HDRS scores equal to or less than 7 scores at the end of 8 week of antidepressant treatment. Childhood Trauma Questionnaire (CTQ-SF, 28 item Short Form) was used to evaluate early life stress events taking place before 16 years old. Life Events Scale (LES) was used to evaluate life stress in the past one year. Genomic DNA was extracted by DNA extracting assay. The 6 SNPs of PLCE1 gene (1: rs17109671, 2: rs17109674, 3: rs17417407, 4: rs2274224, 5: rs3765524 and 6: rs2274223) were determined using Illumina Golden-Gate genotyping. All data were analyzed by SPSS 13.0, Unphased 3.0.13 and Haploview 4. 0 software to identify genetic association with antidepressant drug response. Results: The frequencies of rs17109671 (GG genotype or G allele), rs1710974 (AA genotype or A allele) and rs17417407 (CA genotype) carrier were significant less in non-remitters than in remitters after adjust by gender. 4 haplotypes [G-C (SNP1-4), G-A-C (SNP1-2-6), G-C-G (SNP1-4-5) and A-C-G-A (SNP2-4-5-6)] frequencies were significantly higher in remitters than in non-remitters (all P values were less than values after permutation correction by 1000 simulations). There were no significant difference of distribution of genotype, allele and haplotypes between response and non-response group. 188 patients finished the LES and CTQ-SF. The total and factors scores of LES and CTQ-SF were no significantly different between remitters and non-remitters or between responders and non-responders. The only interaction of PLCE1 gene polymorphism (rs2274224) and child adversity factors was found significantly association with remission to antidepressant. For responders, there were no significant interactions between 6 SNPs and environment factors. Conclusions: The present study suggests a possible effect of PLCE1 gene (rs17109671, rs1710974 and rs17417407 polymorphisms) in the efficacy of antidepressant. The interaction of rs2274224 polymorphisms of PLCE1 gene and childhood adversity could influence the antidepressant outcome. These findings may contribute to our understanding of variation of antidepressant efficacy in patients with depression.