Effect Of BDNF Val66met Polymorphism, PlCE1 Gene, Environmental Factors And Their Interactions On Clinical Antidepressant Treatment Outcome

ObjectiveThe clinical remission of antidepressant treatment was low with a long incubation period, but the mechanism is unclear. Several studies showed antidepressant could influence intracellular signal transduction, regulate of nerve cell growth, proliferation, survival and neural plasticity by acting on monoamine receptors. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic family known to regulate neuronal plasticity and survival, may play an important role in the mechanisms underlying antidepressant therapeutic action. BDNF could active mitogenactivated protein kinase (MAPK) pathway, which participated in the mechinsim of antidepressant, through coupling with tyrosine kinase (Trk). Recent studies showed antidepressant could modulate phosphoinositide (PI) by interacting with the phospholipase C (PLC). Phospholipase C epsilon (PLCε) is a member of PLC families, which was initially characterized as a novel Ras-binding protein. PLCεwas not only the enzyme to odulate PI signal transduction, but also a indirect mediator of MAPK signal transduction though Ras, which participate in the mechanism of depression and may be the target of the antidepressant action. The aim of this study was to examine the associations of antidepressant treatment with BDNF Val66Met polymorphism, PLCE1 gene, environment factors and their interactions.MethodsWe recruited 340 patients of major depressive disorder (MDD) who met the diagnosis criteria of MDD (DSM-IV Axis I). 302 patients of them were finished 8 weeks antidepressant treatment. The severity of depression was measured with the Hamilton Depression Rating Scale (HDRS) before and after 2 weeks, 4 weeks, 6 weeks and 8 weeks antidepressant treatment. 188 patients finished Childhood Trauma Questionnaire, 28 item Short Form (CTQ-SF) and Life Events Scale (LES) which were used to evaluate childhood adverse and life stress before onset. Using Illumina GoldenGate genotyping to determine BDNF Val66Met polymorphism and the 6 SNPs (1: rs17109671, 2: rs17109674, 3: rs17417407, 4: rs2274224, 5: rs3765524 and 6: rs2274223) of PLCE1 gene. Clinical response to 4 weeks antidepressant treatment was considered when a decrease of at least 50% in the baseline HDRS scores. The remission criterion was HDRS scores equal to or less than 7 scores by the end of 8 weeks of treatment. We doing the statistical analysis used by SPSS package software for Windows version 11.0, UNPHASE the version 3.0.13 program and Multifactor Dimensionality Reduction (MDR) program.ResultsThere was no significant difference of genotype and allele distributions for the BDNF Val66Met polymorphism between responders and non-responders or remitters and non-remitters (P=0.943 and 0.754, P=0.890 and 0.845, respectively). The frequencies of rs17109671 A allele carriers were significant higher in non-responders than responders (P=0.048), but the AA genotype and A allele carries were significant more in non-remitters than remitters (P=0.013 and 0.004, respectively). The frequencies of rs17109674 G allele and GG genotype carriers were significant higher in non-remitters than remitters (P=0.001 and 008, respectively). Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) displayed higher frequencies in responders and non-responders (PA-C=0.0049, PA-G-C=0.0033, PA-C-G=0.0031, PG-C-G=0.0065 and PA-C-G-A=0.0043, respectively). 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 (PG-C=0.0025, PG-A-C=0.0020, PG-C-G=0.0026 and PA-C-G-A=0.0013, respectively). No significant unification between BDNF Val66Met polymorphism and PLCE1 gene was found effect on antidepressant treatment. But there was no significant difference of CTQ scores and LES scores between responders and non-responders or remitters and non-remitters. The binary logistic regression analysis showed no interaction between BDNF Val66Met polymorphism and environment significantly effect on antidepressant treatment. But an interaction of rs2274224 polymorphism with childhood adversity factors was found significantly associated with remission to antidepressant.ConclusionsThe rs17109671 A allele carriers were with a poor response efficacy of 4 weeks antidepressant treatment. The rs17109671 (AA genotype and A allele) and rs1710974 (GG genotype and G allele) carriers were with a poor remission of 8 weeks antidepressant. Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) were asocciated with better response efficacy of 4 weeks antidepressant treatment. 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) were associated with better remission of 8 weeks antidepressant. The interaction of rs2274224 polymorphism and child adversity might be effect on 8 weeks antidepressant outcome. But there were no effect of BDNF Val66Met polymorphism, recently life adverse events, childhood adversity, and the interactions of BDNF Val66Met polymorphism and environment factors on short term antidepressant outcome.