COL1A1基因PCOL2和Sp1结合位点多态与先天性髋脱位的关联分析

目的 研究Ⅰ型胶原a1链(collagen type Ⅰ alpha 1，COL1A1)基因PCOL2和Sp1结合位点多态性在中国北方人群中的分布，并探讨其与先天性髋脱位(congenital dislocation of the hip，CDH)的关系。方法 在81个CDH核心家系的243名成员中，采用聚合酶链反应-限制性片段长度多态性分析方法，对位于COLIAI基因启动子内的PCOL2多态(-1997G／T)和转录调控区第1内含子内的Sp1多态(1546G／T)进行基因分型，并进行传递不平衡检验。结果COL1A1，基因PCOL2结合位点G／T多态与CDH不存在明显关联(P=0．537)，中国人PCOL2多态位点的基因型和等位基因频率分布与西班牙白人群和美国白人群差异存在统计学意义；Sp1结合位点只检测到SS基因型，未检测到Ss或ss基因型。结论 COL1A1基因PCOL2和Sp1结合位点多态存在种族差异，PCOL2和Sp1结合位点多态可能与中国人CDH的发病风险无关。     

5-HTR2A基因启动子区-1438G/A多态性与抗精神病药源性肥胖的核心家系关联研究

目的探讨中国汉族首发精神分裂症(schizophrenia,SCH)患者抗精神病药物(antipsychoticagents,APS)治疗过程中体重增加是否与五羟色胺2A受体(5-hydroxytryptamine2Areceptor,5-HTR2A)基因启动区-1438G/A多态性相关。方法对84例首发精神分裂症患者(包含完整核心家系70个)APS(氯丙嗪或利培酮)单药治疗10周,治疗前后测量体重并计算体重指数。采用聚合酶链反应-限制性片段长度多态技术分析5-HTR2A基因启动区-1438G/A多态性基因型和等位基因分布频率,进行APS所致体重增加与5-HTR2A基因启动区-1438G/A多态性的相关分析、传递不平衡检验及数量性状传递不平衡检验。结果治疗10周后患者体重较基础体重增加(8.00±6.13)%。APS治疗10周后,体重增加≥7%和<7%患者组间,5-HTR2A基因-1438G/A多态性各基因型和等位基因分布频率差异均无统计学意义(P>0.05)。5-HTR2A基因-1438G/A多态性的各基因型之间各项指标的差异均无统计学意义(P>0.05);同时未发现5-HTR2A基因-1438G/A在不同体重增加组间存在传递不平衡。结论5-HTR2A基因-1438G/A多态性可能不是影响APS所致体重增加的主要遗传因素。     

神经型烟碱乙酰胆碱受体α7亚单位基因多态性与精神分裂症的传递不平衡研究

目的 探讨神经型烟碱乙酰胆碱受体α7亚单位基因(neuronal nicotinic acetyleholine receptor α7 subunit gene,CHRNA7)多态性与精神分裂症的关系.方法 应用聚合酶链反应及聚丙烯酰胺凝胶芯片技术检测129个精神分裂症先证者核心家系CHRNA7基因的rs2337980、rs1909884、rs883473三个单核苷酸多态性,并采用基于单倍型的单倍型相对风险检验(haplotype relative risk,HHRR)、传递不平衡检验(transmission disequilibrium test,TDT)及单倍型分析进行统计.结果 (1)HHRR分析结果显示rs2337980位点精神分裂症患者组与虚拟对照组之间等位基因频率差异有统计学意义(P=0.017);(2)TDT分析发现,rs2337980位点与精神分裂症之间可能存在传递不平衡,杂合子父母过多的传递等位基因C给患病子女(P=0.021).(3)单倍型分析发现,rs2337980、rsl909884及rs2337980、rsl909884、rs883473组成的单倍型与精神分裂症有显著相关(总体P=0.034;glohal P=0.027),其中T-C,T-C-T两个单倍型与精神分裂症可能存在传递不平衡.结论 CHRNA7 基因多态性可能与精神分裂症存在关联,rs2337980的变异等位基因T可能是精神分裂症的保护性因子.     

Neuregulin 1基因多态性与中国汉族精神分裂症关联分析

目的 探讨Neuregulin 1(NRG1)基因多态性与精神分裂症的关联.方法 在258个中国汉族精神分裂症核心家系(患者及其亲生父母)中,应用实时定量PCR技术检测位于NRGl基因5'端的4个单核苷酸多态(single nucleotide polymorphism,SNP)位点:rs221533(C/T)、rs7820838(C/T)、433E1006 (A/G)和rs3924999(C/T),进行基因分型,应用传递不平衡检测(transmission disequilibrium test,TDT)分析等位基因传递情况,分析该基因与精神分裂症易感性的关联.结果 在258个中国汉族核心家系中,rs221533、433E1006、rs3924999三个SNP均存在有统计学意义的传递不平衡,优先传递的等位基因分别是:C、A、T(rs221533:X2=27.45,P=0.000;433E1006:X2=56.08,P=0.000;rs3924999:X2=10.53,P=0.001).rs7820838未检到不平衡传递(X2=3.31,P=0.081).频率大于1%单倍型进行分析,rs221533-rs7820838-433E1006联合分析,单倍型C/C/G和C/C/A优先传递(C/C/G:X2=5.26,P=45.08;C/C/A:X2=0.026,P=0.000);rs221533-rs7820838-433E1006-rs3924999联合分析,单倍型C/C/G/T、C/C/A/C和C/C/A/T优势传递(C/C/G/T:X2=10.71,P=0.001;C/C/A/C:.)X2=8.83,P=0.006、C/C/A/T:X2=27.00,P=0.000).213个阳性亚型的精神分裂症核心家系中传递不平衡得出基本一致的结果 .结论 Nrg1基因多态性与中国汉族人群精神分裂症存在关联,尤其是支持与阳性亚型精神分裂症存在关联.     

FXYD6基因遗传多态性在精神分裂症患者核心家系中的传递不平衡检验

目的 探讨FXYD6基因单核苷酸多态性(single nucleotide polymorphisms,SNP)和精神分裂症(schizophrenia)之间的相关性.方法 采用等位基因特异性PCR的方法对FXYD6基因6个SNPs(rs10790212、rs11544201、rs555577、rs1815774、rs4938446和rs497768)位点的基因型在101个三口之家中进行传递不平衡检验(transmission disequilibrium test,TDT).结果 遗传标记rs10790212和rs11544201显示了显著的传递不平衡(P＜0.05),而单倍型分析的结果表明单倍型rs10790212-rs11544201与精神分裂症显著性关联(P＜0.05).结论 FXYD6基因与中国汉族人群精神分裂症遗传易感性相关,有必要进一步开展对FXYD6基因的功能学研究.     

5-羟色胺转运体基因启动子区CpG岛甲基化状态与精神分裂症Ⅰ型和Ⅱ型的关联

目的:探讨5-羟色胺转运体(5-HTT)基因启动子区CpG岛甲基化状态与精神分裂症Ⅰ型和Ⅱ型的关联。方法:运用特异性甲基检测PCR和直接测序法对62例精神分裂症Ⅰ型患者、38例Ⅱ型患者和50例健康被试5-HTT基因启动子区CpG岛甲基化状态进行检测。结果:三组5-HTT基因启动子区CpG岛甲基化阳性率无显著性差异;精神分裂症Ⅰ型患者5-HTT基因启动子区CpG岛内位点甲基化率显著高于精神分裂症Ⅱ型患者和健康被试组。结论:5-HTT基因启动子区CpG岛内位点高甲基化可能是精神分裂症Ⅰ型的发病机制之一。     

强迫症药物疗效与六个功能基因的分子遗传药理学研究

目的　探讨与5-羟色胺系统和多巴胺系统有关的6个基因(5-羟色胺2A受体基因、5-羟色胺转运体基因、多巴胺D2受体基因、多巴胺D4受体基因、儿茶酚胺氧位甲基转移酶基因、单胺氧化酶A基因)与强迫症药物疗效之间是否存在关联。方法　收集了113个强迫症核心家系,对强迫症患者给予5-羟色胺回吸收抑制剂治疗,采用Yale-Brown强迫量表在治疗8周前后进行评定,按Yale-Brown强迫量表评分分为有效组和无效组。采用限制性片段长度多态性和可变数串联重复序列多态性技术对有效组和无效组的强迫症家系在6个基因的7个位点上进行传递不平衡检测。结果　未发现6个基因与不同药效的强迫症家系之间存在关联,但发现有效组和无效组在5-羟色胺2A受体基因-1438G/A位点基因型频率存在差异,无效组有更多的纯合子(χ2=4.69,P=0.03)。结论　5-羟色胺2A受体基因可能和强迫症药物治疗效果有关。     

基于家系的Tim-1基因启动子多态性与儿童过敏性哮喘的关联研究

目的:以家系资料为基础,利用遗传不平衡原理探讨染色体5q31-33区Tim-1基因启动子3多态性-2562GA、-416CG和-232GA与湖北地区汉族儿童过敏性哮喘的关系。方法:应用限制性片段长度多态性技术分析了118个儿童过敏性哮喘核心家系Tim-1基因-2562GA、-416CG和-232GA多态性位点的基因型;采用基于家系的传递不平衡检验(TDT)分析基因分型数据;应用TRANSMIT软件构建单倍型并进行单体型关联分析。结果:①118个核心家庭TDT分析显示-2562GA、-232GA位点由杂合子父母传递给患病子代的等位基因频率没有偏离50%,差异无显著性(P0.05),-416CG位点由杂合子父母传递给患病子代的G等位位点的观察值明显高于期望值(P0.05)。②TRANSMIT单体型传递不平衡分析显示父母传递给患病子女GCA和GGA单体型的观察值与期望值差异有显著性(P0.05);Globalχ2检验结果显示Tim-1的单体型与儿童过敏性哮喘有关联(χ2=17.26,P0.01)。结论:Tim-1基因启动子的-416CG位点与中国湖北地区汉族儿童过敏性哮喘易感性相关,由其构建的单体型也与哮喘相关。Tim-1基因遗传多态性可能在哮喘的发病中起重要的作用。     

我国汉族人群α1基因数目可变串联重复序列分布特征的研究

目的：研究我国汉族人群免疫球蛋白α1基因中3个数目可变串联重复序列(VNTR)多态性分布特征，及其与已报道的高加索人群相比较的特点。 方法: 从现存数据库中寻找α1基因内的3个VNTR位点，即α1基因3’端的hs1,2增强子内的VNTR1、其上游6 Kb 的VNTR2和位于α1基因第5外显子的E5VNTR。 提取201例广东汉族人基因组DNA，PCR分别扩增含上述3个VNTR位点片段，2%－3％凝胶电泳分带鉴定基因型，并以测序证实。 结果: 与高加索人群比较我国汉族人群α1基因 VNTR1多态性分布特征表现为：C（3次重复）等位基因频率明显升高（10.0% vs 1.0%）， A（1次重复）等位基因频率偏低（30.3% vs 36.1%-39.4%）, 差异显著（χ2=72.85，P＜0.01）。 基因型BB占37.8％， AB占32.3％，AA占12％，BC占11.4％, AC占4.5％, CC占2.0％， BC、AC基因型分布频率显著高于高加索人群，而AB型分布频率显著低于高加索人群（χ2=73.77，P＜0.01）。另外两个数据库中报道的VNTR位点（VNTR 2及E5VNTR）在我们所测人群中呈均一分布,PCR产物长度分别为136 bp(VNTR 2)和535 bp(E5VNTR)。 结论: 我国汉族人群α1基因 VNTR多态性分布与基因组数据库中基于高加索人群的资料不尽相同，其中Iα1 hs1,2 VNTR1多态性不同于高加索人群，突出表现为C等位基因频率及BC、AC基因型频率显著高于高加索人群。而VNTR2和E5VNTR在被检人群中未见多态性。本研究弥补了现存数据库中缺乏我国汉族人群相应数据的不足, 同时为以α1基因为候选基因找寻疾病基因的研究提供了可靠的数据。     

肿瘤坏死因子α基因(TNFα)-G308A多态性与精神分裂症的关联

目的：探讨肿瘤坏死因子α基因(TNFα)—G308A多态性与精神分裂症的关系。方法：收集141个核心家系，每家有1名符合ICD-10精神分裂症诊断标准的患者，患者的生物学父母均健在；用聚合酶链式反应-限制性片段长度多态性(PCR-based RFLP)分析方法检测所有研究对象的TNFα-G308A基因型。结果：传递不平衡检验(TDT)显示等位基因的传递具有统计学显著性差异(χ2TDT＝7．7044，P＝0.005)。结论：肿瘤坏死因子α基因(TNFα)-G308A多态性与精神分裂症相关联，支持肿瘤坏死因子。基因(TFNα)是精神分裂症的候选基因。     

No evidence for interaction between 5-HT2A receptor and serotonin transporter genes in schizophrenia

This study was to aim at investigating the potential interaction for the serotonin receptor gene (5-HTR) 2A and serotonin transporter gene (5-HTTLPR) polymorphisms in the development of schizophrenia, as well as the interaction of the two polymorphisms in relation with symptomatology, family history, age of onset and antipsychotic response. Genomic DNA analysis with polymerase chain reaction (PCR) was used for the genotyping. One hundred and eleven (111) patients with schizophrenia and 172 normal controls participated in the study. We did not find any association between the individual polymorphism and schizophrenia. The significant interaction effect between 5-HTTLPR and 5-HTR2A polymorphisms on the development of schizophrenia as well as on the antipsychotics response, family history, symptomatology and age at onset, was not found. However, subject with 5-HTR2A*TT genotype were found to have lower age of onset, compared to their counterparts (p=0.01). These results suggest that the interaction between 5-HTTLPR and 5-HTR2A polymorphisms may not contribute to susceptibility to schizophrenia as well as some clinical factors such as antipsychotic response, at least in the Korean population.     

Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients

Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P = 0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P = 0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency.     

No association between serotonin transporter gene polymorphisms and personality traits.

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.     

Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

Sixty-two patients with schizophrenia and 96 normal controls were investigated for genetic association with restriction fragment length polymorphisms (RFLPs) in the serotonin receptor genes. A positive association between the serotonin 2A receptor gene (HTR2A) and schizophrenia was found, but not between schizophrenia and the serotonin 1A receptor gene. The positive association we report here would suggest that the DNA region with susceptibility to schizophrenia lies in the HTR2A on the long arm of chromosome 13. © 1996 Wiley-Liss, Inc.     

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:430–436, 1999. © 1999 Wiley-Liss, Inc.     

Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (-1438 A > G and His452Tyr) in the serotonin 5-HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A -1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies.     

Interaction of serotonergic and noradrenergic gene variants in panic disorder

OBJECTIVE: Panic disorder is an anxiety disorder with an estimated heritability of 48%. Associations findings have been obtained with candidate genes from both serotonergic and noradrenergic pathways including regulatory and coding variants of the serotonin receptor 1A gene, the monoamine oxidase A gene, the catechol-O-methyltransferase gene and the norepinephrine transporter gene. METHODS: In the present study, an analysis of interactions between the functional serotonin receptor 1A polymorphism, the norepinephrine transporter variants and the other respective polymorphisms of the above-mentioned genes is reported. The analysis is based on genotype results from 115 cases and 115 age and sex-matched controls. RESULTS: A nominally significant (P=0.04) interaction between the serotonin receptor 1A and the catechol-O-methyltransferase polymorphisms was observed. Stratified analysis revealed that the odds ratio of each polymorphism was highest in the presence of the low-risk genotype(s) of the other polymorphism and low in the presence of the high-risk genotype(s) of the other polymorphism. CONCLUSIONS: This is the first possible interaction of genetic variations in panic disorder that has been observed. As the sample size was small and no adjustment for multiple testing was made, the assessment of the interacting risk alleles needs replication in a larger sample with higher power.     

No association between polymorphisms in the DDC gene and paranoid schizophrenia in a northern Chinese population

Several lines of evidence suggest that dysfunctions of neurotransmitters are associated with schizophrenia. DOPA decarboxylase (DDC) is an enzyme involved directly in the synthesis of dopamine and serotonin, and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered a candidate gene for schizophrenia. We performed an association study between three single nucleotide polymorphisms in the DDC gene and paranoid schizophrenia. However, in our study no significant differences were found in the genotype distributions and allele frequencies between 80 paranoid schizophrenics and 108 controls for any of the polymorphisms. Neither did the haplotypes of the single nucleotide polymorphisms show any association with paranoid schizophrenia. Therefore, we conclude that the polymorphisms studied do not play a major role in paranoid schizophrenia pathogenesis in the population investigated.     

The modulatory influence of polymorphism of the serotonin transporter gene on characteristics of mental maladaptation in relatives of patients with endogenous psychoses

A number of studies have reported an association between 5-HTTLPR, a polymorphism of the serotonin transporter gene, and the development of depressive states in response to a variety of distal and proximal stressors. We report here studies of the effects of the 5-HTTLPR polymorphism on the probability that an individual will develop mental maladaptation in 224 close relatives of patients with severe chronic mental disorders — schizophrenia and schizoaffective and affective psychoses. The ss genotype of the serotonin transporter gene contributes to the formation predominantly of manifestations of distress, reflected by increases on the hypochondriasis scale of the MMPI scale of factors such as the extent of the autonomic component of anxiety reactions and increased attention to own health, as well as increases in sensitivity. At the same time, the ss genotype was less likely to influence the appearance of depression and anxiety, as determined on the depression scale. These tendencies were more marked in males than females. Furthermore, males with the ss genotype were characterized by some increase in tension, suspicion, detachment, and attention difficulty (on the paranoia and schizophrenia scales). These data can be regarded as supporting the role of the short allele of the serotonin transporter gene in enhancing and modulating psychopathological reactions to chronic stress situations in relatives of mental patients. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 107, No. 1, pp. 46–51, January, 2007.     

Serotonin transporter gene polymorphisms and chronic illness of depression

Clinical course of depression is variable. The serotonin transporter gene is one of the most studied genes for depression. We examined the association of serotonin transporter gene polymorphisms with chronicity and recurrent tendency of depression in Korean subjects. This cross-sectional study involved 252 patients with major depression. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), s/l variation in second intron of the 5-HTT gene (5-HTT VNTR intron2). Chronicity was associated with 5-HTTLPR. Patients with l/l had higher rate of chronicity than the other patients (l/l vs s/l or s/s; odds ratio, 4.45; 95% confidence interval, 1.59-12.46; P=0.005; logistic regression analysis). Recurrent tendency was not associated with 5-HTTLPR. Chronicity and recurrent tendency were not associated with 5-HTT VNTR intron2. These results suggest that chronic depression is associated with 5-HTTLPR.