Association Study Of NR3C1 And NR3C2 Gene Polymorphisms With Major Depression And Pharmacogenomics Of Venlafaxine

BACKGROUND:Major depressive disorder(MDD)is a mental disorder that has huge impacts on society and economy.But the pathogenesis underlying it remains unclear.The hypothalamic pituitary adrenal(HPA)axis has been reported abnormal in MDD patients.The glucocorticoid receptor and mineralocorticoid receptor encoded by NR3C1 and NR3C2 play irreplaceable roles in HPA axis.OBJECTIVE:1.To study the relationship between six single nucleotide polymorphisms(SNPs)rs6191,rs6196,rs10482614,rs1512325,rs1512342 and rs2070951 within NR3C1 and NR3C2 and the risk of MDD.2.To study the relationship between NR3C1 and NR3C2 gene polymorphisms and antidepressant efficacy.The aims of this study are to explore the role of NR3C1 and NR3C2 gene polymorphisms in the pathogenesis of MDD and to provide biological predictive indicators for individual antidepressant therapy.METHODS:1.A case-control study was conducted.The case group was consisted of 523 Southern Chinese HAN MDD patients.The control group was 985 Southern Chinese HAN healthy persons.SHEsis,R and GMDR were used to analyze the impacts of these six SNPs on the risk of MDD.2.Patients with MDD who met the enrollment criteria were treated with venlafaxine for six weeks.The Hamilton Depression Scale(HAMD)score was calculated evaluate the therapeutic effect.At the end of the 6th week,the patients were divided into the response group(reduction rate?50%)and the non-response group(reduction rate<50%).And according to the HAMD of the sixth weekend,the patients were divided into the remission group(HAMD-6?7)and non-remission group(HAMD-6>7).The effects of six SNPs on venlafaxine treatment outcome were investigated by SHEsis,R and GMDR analysis.4.Investigate the effect of thyroid stimulating hormone(TSH)and adreno cortico tropic hormone(ACTH)on venlafaxine treatment outcome.5.The change the endocrine index was set as an internal phenotype to study relationship between this internal phenotype and NR3C1 and NR3C2 gene polymorphisms.6.R,t test,?2 test and five genetic models were used in this study.SHEsis was used to calculate the allele frequency and genotype frequency,Hardy-Weinberg Equilibrium p-value and odds ratio(OR).GMDR was used for gene interaction analysis.RESULTS:1.There was no significant difference in the allele and genotype frequencies of the these six SNPs between the MDD group and the healthy group(p>0.05).2.During venlafaxine treatment,the HAMD scores of patients with rs1512325 T/T genotype declined faster than patients with C/T and C/C(p<0.001).In addition,the HAMD score of patients with rs6196 G/G genotype was also declined faster than others(p=0.003).After gender stratification,the result has only been maintained in men(prs6196=0.038,prs1512325<0.001).3.The rs1512325 allele frequency and genotype frequency were significantly different between remission and non-remission.T allele in the remission group was significantly higher(p=0.015,OR=1.873,95%CI=[1.13-3.10]).T/T genotype frequencies were significantly higher in the remission group(p=0.03).The dominant model is the best fit one by five genetic model analysis.After gender stratification,this result only survived in men.There is a strong interaction between rs1512325,rs1512342 and rs6191.Males with C/C-T/C-G/G(rs1512325-rs1512342-rs6191)genotype could more easily remitted from MDD after treated with venlafaxine.4.After treated with venlafaxine,the level of TSH significantly declined in the non-remission group and increased in the remission group(p=0.004).After gender stratification,this difference has only been manifested in males(p=0.027).5.In males,there were no statistically significant differences in the allele frequency and genotype frequenccy between TSH levels' increasing and decreasing.CONCLUSION:The three SNPs within NR3C1(rs6191,rs6192 and rs10482614)and the three SNPs within NR3C2(rs1512325,rs1512342 and rs2070951)may not be associated with the risk of MDD.In males,the rs1512325 within NR3C2 may have an effect on venlafaxine treatment outcome.When males treated with venlafaxine,the rise of TSH promotes therapeutic effect.However,TSH levels' increasing may not be related to the NR3C1 and NR3C2 gene polymorphisms in males.