Association Study Of SLC6A4 Gene Promoter Region Polymorphisms With Schizophrenia And The Efficacy Of Antipsychotics

Objective Defects in the function of 5-hydroxytryptamine(5-HT)system are the important pathology hypothesis of schizophrenia(SCZ).5-hydroxytryptamine transporter(5-HTT)plays an important role in the regulation of 5-HT content,and is also an important target of antipsychotics.The polymorphic region,located in the promoter upstream of SLC6A4 which encodes 5-HTT,affects gene transcriptional activity.This study focused on schizophrenic patients and healthy population in Han Chinese,screening for variants of the SLC6A4 promoter region,to explore the association between genotypes and SCZ,and the efficacy of antipsychotics.Methods 1.The samples consisted of 624 patients with schizophrenia and 683 healthy controls.The polymorphisms of 5-HTTLPR and rs25531 were genotyped with PCR agarose gel electrophoresis and PCR-RFLP.TA cloning and Sanger sequencing confirmed the specific nucleotide sequence.2.Schizophrenic patients were treated with atypical antipsychotics for 8 weeks.At baseline and week 8,the severity of symptoms were evaluaded by the PANSS.Extrapyramidal symptoms(EPS)were evaluaded using Simpson-Angus Scale(SAS).3.The results of genotyping and clinical data were analyzed using SPSS16.0.Results 1.5-HTTLPR includes two common variations,short(S,14 repeats)allele and long(L,16 repeats)allele,respectively accounted for 70% and 25%.In addition,we found 5 kinds of extra long(XL,17,18,20,22 and 26 repeats)alleles in our study population,and the 26 repeats has never been reported.rs25531 occurs only in L allele,which leads to the appearance of the allelic subtypes LA and LG.2.There were significant difference between cases and controls on genotype frequencies of 5-HTTLPR.S/XL genotype is a risk factor for schizophrenia(P=0.042,OR=1.79,95%CI: 1.01-3.17).The genotype frequencies of 5-HTTLPR-rs25531 genotype were significant difference between cases and controls.S/XLA,LG/XLA genotypes are risk factors for schizophrenia(P=0.042,OR=1.79,95%CI: 1.01-3.17.P=0.034,OR=3.69,95%CI: 1.01-13.48).3.Between the 5-HTTLPR-rs25531 genotypes,the reduction score of Positive Scale(P)and General Psychopathology Scale(G)had significant difference(P = 0.05,P = 0.008).Improvement of positive symptoms and general psychopathology symptoms of High transcriptional activity group(S/LA,LA/LG,S/XLA,LG/XLA,LA/LA)were better than the low transcriptional activity group(S/S,S/LG,LG/LG).Between the 5-HTTLPR-rs25531 alleles,the reduction score of G had significant difference(P = 0.007).Improvement of general psychopathology symptoms of High transcriptional activity group(LA,XLA)were better than the low transcriptional activity group(S,LG).4.There were no significant difference in the occurrence frequency of EPS and the severity of EPS between 5-HTTLPR-rs25531 genotypes and alleles(P>0.05).Conclusions The polymorphisms of 5-HTTLPR-rs25531 in the promoter of SLC6A4 are associated with the susceptibility of schizophrenia,as well as atypical psychotropics efficacy,but not related with EPS in Han Chinese population.