Association Study Of 5-HT_2A Receptor,NET,FKBP5 Gene Polymorphisms With Major Deprssive Disorder And Antidepressants Treatment Response

Objective:(1) To prove the predictive biological items of personal treatment of major depressive disorder by investigating the association between the rs6311 polymorphism of serotonin receptor 2A (5-HT_2A) gene,the rs5569 polymorphism of norepinephrine transporter (NET) gene and the rs3800373,rs1360780 polymorphisms of FK506-binding proteins 5 (FKBP5) gene and the therapeutic response,the side-effect of antidepressant drugs.(2) To probe the role in major depressive disorder genetic mechanism of the four SNPs (rs6311,rs5569,rs3800373,rs1360780) by exploring the association between them and major depressive disorder.(3) To investigate the predictive clinical factors of response to antidepressant drugs.Methods:(1) 263 major depressive disorder patients who met DSM-IV criterion were given antidepressant drugs for six weeks (SSRIs: citalopram,parxetine, SNRIs: venlafaxine,dutoxetine). They were surveyed with the situation of demography, past history and family history, while they were also elevated by Hamiltion Depression Scale (HAMD, 17 items),Hamiltion Anxiety Scale (HAMA),the Brief Psychiatric Rating Scale (BPRS),Clinical Global Impression (CGI),Minnesota multiphase personality inventory (MMPI),Life Events Scale (LES),, Automatic Thoughts Questionnaire (ATQ) and Treatment Emergent Symptom Scale (TESS) . The patients were divided into two groups of the responder group and the non-responder group, according to the decreasing rate of score of HAMD≥50% and <50% respectively. The differences of the four SNPs polymorphisms and the clinical factors between the responder group and the non-responder group were analyzed.(2) With the case-control design, 263 major depressive disorder patients and 237 controls were matched in the ratio of age and gender. The relationship between the four SNPs and major depressive disorder were analyzed.(3) The ligase detection reaction was used to detect the SNPs of rs6311,rs5569,rs3800373 and rs1360780.(4) All analyses were conducted with SPSS15.0 for Windows. We used t-test, chi-square test, analysis of variance, logistic regression analysis, and odds ratio according to the type of the data. The haplotype model was constructed with SHEsis on-line. Results:(1) Relationship between 5-HT_2A receptor gene rs6311 polymorphism and antidepressant response: The frequencies of T allele and TT genotype of rs6311 were higher in non-responder group than that in responder group for SSRIs therapy (P<0.05, P<0.01). In the SSRIs therapy group, the HAMD decreasing score and decreasing score rate of the paitents with TT genotype of rs6311 were lower than the paitents with CC genotype of rs6311 (P<0.05).(2) Relationship between NET gene rs5569 polymorphism and antidepressant response: The frequencies of C allele and CC genotype of rs5569 was lower in non-responder group than that in responder group for SNRIs therapy (P<0.05, P<0.01). In the SNRIs group, the HAMD decreasing score and decreasing score rate of the paitents with CC genotype of rs5569 were higher than the paitents with TT genotype of rs5569 (P<0.05).(3) Relationship between FKBP5 gene rs3800373 and rs1360780 polymorphisms and antidepressant response: There were no significant differences in the genotype and allele frequencies of FKBP5 gene rs3800373 and rs1360780 polymorphisms between responder group and non-responder group (P>0.05). Not only in the SSRIs but also in the SNRIs therapy group, the genotype and allele frequencies of rs3800373,rs1360780 were no significant differences between responders and non-responders (P>0.05). No significant differences were found in rs3800373-rs1360780 haplotypes frequencies and frequency compositions between responder group and non-responder group (P>0.05).(4) Relationship between the four SNPs (rs6311,rs5569,rs3800373,rs1360780) and the side-effect of antidepressant drugs: there were no significant differences in the incidence rate of total side effect and nausea adverse effect between the paitents with difference genotypes of rs6311,rs5569,rs3800373 and rs1360780(P>0.05).(5) In case-control association analysis, no significant differences were found in genotype and allele frequencies of the four SNPs (rs6311,rs5569,rs3800373,rs1360780) between case and control (P>0.05). Using haplotype analysis, rs3800373 and rs1360780 were in strong linkage disequilibrium (D'=0.970, r²=0.914). No significant differences were found in rs3800373-rs1360780 haplotypes frequencies and frequency compositions between case and control (P>0.05).(6) When stratified by gender,family history and first episode, the genotype distributions of four SNPs (rs6311,rs5569,rs3800373,rs1360780) were no significant differences (P>0.05).(7) Relationship between clinical characteristics and antidepressant response: Logistic regression analysis showed that family history, anxiety symptoms and long durations entered into the regression equation(OR=6.336,5.749,1.024).Conclusion:(1) The rs6311 of 5-HT_2A receptor gene may be related with the treatment response to SSRIs, T allele and TT genotype is likely to be a predictive factor of the worse treatment reponse to SSRIs.(2) The rs5569 of NET gene may be related with the treatment response to SNRIs, C allele and CC genotype is likely to be a predictive factor of the better treatment response to SNRIs.(3) The rs3800373 and rs1360780 of FKBP5 gene may be not asscoiated with the antidepressant treatment response.(4) The four SNPs of rs6311,rs5569,rs3800373 and rs1360780 may be not asscoiated with the side effect of antidepressant drugs.(5) There were no association between major depressive disorder and the four SNPs of rs6311,rs5569,rs3800373 and rsl360780, which suggested that 5-HT_2A receptor,NET and FKBP5 genes may have no association with major depressive disorder.(6) Family history, anxiety symptoms and long durations may be affected the antidepressant treatment effect.