代谢型谷氨酸受体3基因多态性与中国北方汉族男性酒依赖关系的研究

目的探讨中国北方汉族人群代谢型谷氨酸受体3(GRM3)基因多态性与酒依赖的相关性。方法采用聚合酶链反应(PCR)和连接酶检测反应(LDR)方法,检测248例酒依赖患者和235例对照组的GRM3组基因上10个位点的单核苷酸多态性。结果酒依赖组与对照组相比较,rs6465084位点的A等位基因和A/A基因型频率明显增高(P0.05)。单体型TAATATT、CAGTATT、TCGTATT、CAATAGC、TAATATC频率在酒依赖组和对照组中具有统计学显著差异(P0.05),其中单体型TAATATT频率较对照组明显增高(P0.001),且频率≥5%。结论GRM3基因可能是酒依赖发生的候选基因之一。     

脑啡肽酶基因多态性与散发性阿尔茨海默病的关系研究

目的探讨脑啡肽酶(neprilysin,NEP)基因单核苷酸多态性与中国北方汉族散发性阿尔茨海默病(sporadic Alzheimer’s disease,SAD)的关系。方法临床确诊的99例中国北方汉族SAD患者及109例正常对照,提取外周血基因组DNA,聚合酶链反应-限制性片段长度多态性结合DNA直接测序法确定NEP基因rs989692位点及rs6776185位点基因型,分析上述两个位点单核苷酸多态性与AD的关系。结果 AD组和正常对照组NEP基因rs989692位点各等位基因频率及基因型分布无显著性差异(P>0.05);AD组NEP基因rs6776185位点A等位基因频率显著高于正常对照组(88.9%vs 81.2%,P=0.029),AA基因型频率显著高于正常对照组(80.8%vs 67.0%,P=0.024);携带A等位基因者,发生AD的风险是不携带A等位基因者的1.85倍(OR=1.85,95%CI 1.07~3.20);经载脂蛋白E基因(apolipoprotein E,Apo E)ε4等位基因及年龄分层比较,携带ε4基因及年龄<75岁组,AD组A等位基因及AA基因型分布频率仍明显高于正常对照组(P<0.05)。结论 NEP基因rs6776185位点A等位基因和AA基因型可能是中国北方汉族人群SAD的危险因素,可使AD发病年龄提前,并与Apo Eε4等位基因可能具有协同作用。     

云南少数民族和汉族特发性癫痫CLCN2基因多态性研究

目的检测云南省5种独有少数民族(基诺族、阿昌族、布朗族、佤族、拉祜族)与汉族人群特发性癫痫与电压门控氯通道-2基因CLCN2基因多态性是否相关。方法采用PCR、单碱基延伸(SNap shot)等技术,应用病例-对照法检测云南少数民族特发性癫痫患者92例及其未发病亲属170例、云南汉族特发性癫痫患者107例及63例健康人群外周血CLCN2基因多态性。统计少数民族与汉族人群中rs13099401、rs4912540两个位点的基因型、等位基因频率,分别用χ2等检验进行统计分析。结果 CLCN2基因rs13099401位点基因型频率分布在少数民族病例组与汉族病例、对照组之间有统计学差异(χ2=6.828,P=0.033;χ2=9.246,P=0.010,均P<0.05);基因型CC与非CC型在少数民族病例组与汉族对照组间有统计学差异(χ2=9.245,OR=3.26,P=0.002,P<0.01)。rs4912540位点基因型频率在各组间无统计学差异(P>0.05)。结论 CLCN2基因位点rs13099401可能是云南少数民族特发性癫痫患者的相关性位点,基因型CC为汉族特发性癫痫发作的一个保护性因素;rs4912540与云南人群特发性癫痫无显著相关性。     

DVL2基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联研究*☆◇

背景：近20年来小鼠的分子胚胎学研究进展获得了大量关于脊椎发育的分子信息,用同线性分析法确立先天性脊柱侧凸的候选基因已成为可能。 目的：通过候选基因DVL2上关键单核苷酸多态性位点的筛查,探索DVL2与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：采用病例-对照研究,入选127例中国汉族先天性脊柱侧凸患者和127例对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取DVL2的标签和功能单核苷酸多态性。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。对所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选5个位点：单核苷酸多态性1(rs2074222)、单核苷酸多态性2(rs222837)、单核苷酸多态性3(rs222835)、单核苷酸多态性4(rs10671352)和单核苷酸多态性5(rs222836),其基因型分布在病例和对照组中均符合Hardy-Weinberg平衡;5个位点处于完全连锁不平衡状态;5个位点的基因型/等位基因/单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性。在进一步与先天性脊柱侧凸临床表型的关联分析中没有发现阳性位点。提示在中国汉族人群中DVL2基因可能不是引起先天性脊柱侧凸及其不同临床表型的主要因素,有待于进一步深入研究。     

他克莫司结合蛋白5基因多态性与抑郁症的关联研究

目的 探讨他克莫司(FK506)结合蛋白5(FKBP5)基因多态性与抑郁症之间的关系.方法 采用高温连接酶检测反应法,检测254例抑郁症患者(患者组)和231名正常对照者(对照组)的FKBP5基因rs3800373,rs1360780 2个位点基因型,分析基因型和等位基因频率在2组间的分布差异,及其与患者临床症状表型之间的关系.结果 (1)患者组FKBP5基因rs3800373位点GG、GT、TT基因型频率分别为4.7％、41.9％、53.4％,对照组分别为6.6％、38.2％、55.3％,2组比较差异无统计学意义(x2=1.252,P＞0.05);患者组FKBP5基因rs1360780位点CC、CT、TT基因型频率分别为55.4％、39.9％、4.7％,对照组分别为56.8％、37.0％、6.2％,2组比较差异无统计学意义(x2=0.739,P＞0.05);FKBP5基因rs3800373和rs1360780 2个位点等位基因频率在2组之间分布的差异无统计学意义(P均＞0.05);(2)单倍型分析显示,rs3800373-rs1360780 2个位点单倍型在患者组和对照组之间分布的差异无统计学意义(P均＞0.05);(3)rs3800373和rs1360780 2个位点不同基因型患者之间汉密尔顿抑郁量表、汉密尔顿焦虑量表和简明精神病评定量表各因子分值的差异均无统计学意义(P均＞0.05).结论 FKBP5基因rs3800373,rs1360780多态性可能与抑郁症缺乏关联.     

NADPH氧化酶p22~(phox)亚基基因多态性与急性动脉硬化性脑梗死的关联性研究

目的探讨CYBA基因的多态性位点与急性动脉硬化性脑梗死的相关性。方法收集284例脑梗死患者(脑梗死组)及335例同期健康体检者(对照组),采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测CYBA基因rs4673和rs3180279位点的基因型。结果 rs4673位点的基因型及等位基因频率分布在脑梗死组和对照组中差异无统计学意义(P0.05)。脑卒中组男性患者rs3180279位点GC、GG基因型的频率低于对照组,CC基因型的频率高于对照组(P=0.034)。结论 CYBA基因的rs4673位点与中国北方汉族人群的急性动脉硬化性脑梗死无相关性,男性rs3180279位点GG+GC基因型的携带者较CC基因型携带者动脉硬化性脑梗死的发病率可能更低。     

细胞色素氧化酶CYP1A2基因多态性与利培酮治疗汉族精神分裂症患者疗效的关联研究

目的:探对细胞色素氧化酶CYP1A2基因多态性与利培酮治疗汉族精神分裂症患者疗效的相关性。方法:给予93例汉族精神分裂症患者单一利培酮治疗12周;治疗前后阳性与阴性症状量表(PANSS)、个人和社会功能量表(PSP)及认知功能评估;采用微测序分型技术(SNa Pshot SNP)检测患者及100名汉族正常对照者(对照组)CYP1A2基因5个位点(rs2069514,rs2472304,rs35694136,rs4646427,rs762551)多态性,分析CYP1A2基因多态性与利培酮疗效的关系。结果:两组间5个多态性位点的基因型、等位基因频率及SNPs单倍型比较差异无统计学意义;5个多态性位点不同基因型患者间的临床疗效比较差异无统计学意义;多重线性回归分析发现部分多态性位点与利培酮治疗精神分裂症后阴性症状、一般病理学症状、PANSS总分、注意转移力、注意集中力的疗效有关。结论:未发现细胞色素氧化酶CYP1A2多态性是汉族精神分裂症的易感基因相关证据;CYP1A2基因多态性与利培酮治疗的疗效相关。     

BACE2多态性位点rs1046210与阿尔茨海默病相关性的研究

目的分析BACE2基因多态性位点rs1046210与中国汉族人群阿尔茨海默病发病的相关性。方法随机选取20例样本对BACE2第7外显子区域进行PCR扩增和直接测序。筛查出中国北方汉族人群中存在的rs1046210变异位点。随后用微测序的方法对348例阿尔茨海默病患者和294例正常对照者进行多态性分型。结果应用SPSS17.0统计软件包进行等位基因和基因型分布的比较,rs1046210C/T位点的基因型和等位基因频率无统计学差异。根据是否携带ApoEε4等位基因进行进一步分层比较,并且应用Logistic回归分析平衡了年龄、性别和ApoE分型的影响后,该位点仍然不具有统计学意义。结论中国北方汉族人群BACE2第7外显子区域多态性位点rs1046210C/T的等位基因和基因型差异与阿尔茨海默病无关。     

中国黑龙江地区汉族人群FK506结合蛋白5基因多态性与精神分裂症的关联研究

目的:探讨中国黑龙江地区汉族人群FK506结合蛋白5(FKBP5)基因多态性与精神分裂症的关系。方法:采用SNaPshot测序法检测和分析49例汉族精神分裂症患者(患者组)和49名汉族健康对照者(对照组)的FKBP5基因rs3800373、rs1360780、rs9296158和rs9470080位点基因型和等位基因频率。结果:FKBP5 rs3800373位点基因型频率两组间差异有统计学意义(P0.05); Logistic回归分析显示,FKBP5基因rs3800373位点TT基因型携带者精神分裂症发生风险明显高于GT基因型携带者(95%CI:0.117～0.756,P=0.01)。结论:FKBP5基因rs3800373位点基因多态性可能与中国黑龙江地区汉族人群精神分裂症发病风险有关。     

Neprilysin基因单核苷酸多态性与阿尔茨海默病的相关性研究

目的探讨neprilysin基因单核苷酸多态性与中国北方汉族散发性阿尔茨海默病(sporadic Alzheimer's disease,SAD)的相关性。方法应用聚合酶链式反应-限制性片段长度多态性方法对157例SAD患者(AD组)和125例正常对照(对照组)进行neprilysin基因rs3736187位点单核苷酸多态性基因分型后,进行病例-对照相关分析。结果基因型的频率在病例组和对照组中分布差别有统计学意义(P<0.05),其中CC基因型与TT基因型相比,AD组CC基因型频率增高,TT基因型频率降低,CC基因型可以增加散发性AD的发病风险(P<0.05)。等位基因频率在两组中的分布差别无统计学意义(P>0.05)。结论Neprilysin基因rs3736187位点的CC基因型可能通过某种途径增加中国北方汉族散发性阿尔茨海默病的发病。     

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms

Recent studies of the association between the metabotropic glutamate receptor 3 gene (GRM3) and schizophrenia have produced conflicting results, although GRM3 is a promising candidate gene. Fujii et al. found a single nuclear polymorphism (SNP) for within this gene, rs1468412 to have a positive association to schizophrenia in Japanese patients. To investigate this further, we genotyped 7 SNPs around GRM3 including rs1468412, in 752 Chinese patients with schizophrenia and 752 controls using Taqman technology. We did not detect any association between rs1468412 and schizophrenia, however we found differences in the allele frequency distribution of SNP rs2299225 (p=0.0297, odds ration [OR]=1.44, 95% confidence interval 1.05-1.99) between cases and controls. Moreover, the overall frequency of haplotypes constructed from three SNPs including rs2299225 showed significant differences between cases and controls (p=0.0017). Our results partially support the previous studies in other ethnic groups and indicate that the GRM3 gene may play an important role in the etiology of schizophrenia in the Han Chinese.     

Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate levels and neurocognition in non-smoking, active alcoholics

ABSTRACT: BACKGROUND: We studied the effects of single nucleotide polymorphisms (SNPs) in the metabotropic glutamate receptor 3 (GRM3) gene on brain N-acetylaspartate (NAA) concentrations and executive function (EF) skills in non-smoking, active alcoholics, and evaluated associations between these variables. METHODS: SNPs (rs6465084, rs1468412, and rs2299225) in GRM3 were genotyped in 49 male, non-smoking, alcohol-dependent patients and 45 healthy control subjects using ligase detection reactions. NAA/creatine (Cr) ratios in left prefrontal gray matter (GM) and white matter (WM), left parietal GM, left parietal WM, and cerebellar vermis regions were measured by Proton 1 H Magnetic resonance spectroscopy (MRS). EF was measured by the Wisconsin Card Sorting Test (WCST). RESULTS: Compared to controls, alcoholics had lower NAA/Cr ratios in prefrontal GM and WM regions and performed more poorly on all EF tests (P < 0.001). Alcoholics with the A/A genotype for SNP rs6465084 had lower NAA/Cr ratios in prefrontal GM and WM regions and had poorer EF skills than alcoholics who were G-carriers for this SNP (P < 0.01). Non-alcoholics with the A/A genotype for rs6465084 also had lower NAA/Cr levels in prefrontal GM and made more random errors in the WCST than G-carriers (P < 0.01). The A/A genotype group for SNP rs6465084 was significantly different from the G carriers for the variables of NAA/Cr ratios and WCST scores in both alcoholics and controls (P < 0.05). Alcoholics who were T-carriers for rs1468412 had lower NAA/Cr ratios in prefrontal GM and showed poorer EF skills (P < 0.05). No effects of rs2299225 genotype on NAA/Cr or executive skills were observed. NAA/Cr in left prefrontal regions correlated with certain parameters of EF testing in both alcoholics and controls (P < 0.05), but the significance of this correlation among alcoholics disappeared after adjustment for the effects of genotype. CONCLUSIONS: Our results provide evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in alcohol dependence. It is possible that certain GRM3 SNP genotypes (the A/A genotype of rs6465084 and the T allele of rs1468412) may further lower NAA/Cr levels and EF skills in addition to the effect of alcohol.     

重性抑郁障碍患者多药耐药基因多态性与帕罗西汀疗效及不良反应的关联研究

目的 探索中国汉族重性抑郁障碍(MDD)患者多药耐药基因(MDR1)多态性与帕罗西汀疗效及药物不良反应的关联.方法 对116例MDD患者给予帕罗西汀治疗,剂量范围20～50mg/d,疗程8周.采用限制性片段长度多态性技术及DNA测序方法检测MDR1基因上5个单核苷酸多态性的基因型,分析各位点基因型及多位点组成的单体型与帕罗西汀临床效应的关系.结果 携带rs1128503位点CC基因型患者的临床缓解率低于其他基因型携带者(TT基因型86.0%,CT基因型72.4%,CC基因型50.0%,P<0.05),且焦虑/躯体化因子减分率较低(P<0.05).携带单体型C-A(rs1128503-rs1202169)患者的临床痊愈率(69.7%)低于非携带者(86.0%),P<0.05.而携带单体型T-A/T-T-G(rs1045642-rs2032582-rs1128503-rs1202169)的患者药物不良反应发生率(29.0%)低于非携带者(49.0%),P<0.05.结论 MDR1基因多态性可能与中国汉族MDD患者帕罗西汀的疗效及不良反应关联.     

No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population

Several lines of evidence have suggested that the metabotropic glutamate receptor 3 (GRM3) gene is a candidate susceptibility gene for schizophrenia. To our knowledge, six studies have investigated the genetic association between GRM3 and schizophrenia, although the results have been quite controversial. In the present study, we investigated the association between the GRM3 gene and schizophrenia in 402 Japanese people by analyzing 10 single nucleotide polymorphisms (SNPs), including all SNPs that showed significant results in previous studies. We observed no significant difference in allelic frequencies or genotypic distributions of the 10 SNPs between the controls and patients. A permutation test showed no significant global differences in estimated haplotype frequencies between the controls and patients. Thus, the present study provides no positive evidence of an association between the GRM3 gene and schizophrenia in the Japanese population.     

Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate measures in the dorsolateral prefrontal cortex

OBJECTIVE: This study was carried out to confirm prior evidence of an effect of a single nucleotide polymorphism (SNP) in the metabotropic glutamate receptor 3 (GRM3) gene (a putative risk factor for schizophrenia) on measures of N-acetylaspartate in healthy comparison subjects. METHOD: Fifty-four carefully screened healthy volunteers genotyped at SNP rs6465084 underwent magnetic resonance spectroscopic imaging (MRSI) at 3 T and selected neuropsychological testing. RESULTS: The A/A genotype group exhibited a significant reduction of N-acetylaspartate/creatine levels in the right dorsolateral prefrontal cortex compared to the G carriers. A tendency in the same direction was seen in the left dorsolateral prefrontal cortex and in the white matter adjacent to the prefrontal cortex. CONCLUSIONS: These findings provide further evidence that GRM3 affects prefrontal function and that variation in GRM3, monitored by SNP rs6465084, affects GRM3 function.     

Association of E-selectin gene polymorphisms with ischemic stroke in a Chinese Han population

The E-selectin gene, a member of the selectin superfamily of adhesion molecules, plays an important role in the pathogenesis of thrombovascular diseases. The present study was designed to investigate the potential relationship between E-selectin gene polymorphisms and ischemic stroke in a Chinese Han population. Three hundred fourteen ischemic stroke patients and 389 unrelated healthy controls were recruited for the study. Three single-nucleotide polymorphisms (SNPs)-rs1805193(G98T), rs5361(A561C), and rs5355(C1839T)-in the exon region of the E-selectin gene, were genotyped using a Multiplex SNaPshot sequencing assay. The data showed that the genotype and allele frequencies of G98T and C1839T SNP were similar in both ischemic stroke patients and the controls. In contrast, the frequency of both the AC genotype and the C allele of A561C was significantly higher in ischemic stroke patients than in healthy controls (P = 0.001, P < 0.001, respectively). After adjusting for other risk factors (such as hypertension, diabetes, tobacco smoking, and alcohol consumption), the E-selectin gene AC genotype and C allele of A561C were still associated with a risk of ischemic stroke (odds ratio [OR] = 2.73, 95% confidence interval (CI): 1.29-5.76, P = 0.008; OR = 2.80, 95% CI: 1.58-4.94, P < 0.001, respectively). Our current study demonstrates that the E-selectin SNP A561C is associated with increased risk for the development of ischemic stroke in this subset of the Han Chinese population.     

No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population

Several lines of evidence have suggested that the metabotropic glutamate receptor 3 (GRM3) gene is a candidate susceptibility gene for schizophrenia. To our knowledge, six studies have investigated the genetic association between GRM3 and schizophrenia, although the results have been quite controversial. In the present study, we investigated the association between the GRM3 gene and schizophrenia in 402 Japanese people by analyzing 10 single nucleotide polymorphisms (SNPs), including all SNPs that showed significant results in previous studies. We observed no significant difference in allelic frequencies or genotypic distributions of the 10 SNPs between the controls and patients. A permutation test showed no significant global differences in estimated haplotype frequencies between the controls and patients. Thus, the present study provides no positive evidence of an association between the GRM3 gene and schizophrenia in the Japanese population.     

A Population-based Association Study of Casein Kinase 1 Epsilon Loci with Heroin Dependence in Han Chinese

Pharmacogenetic studies have confirmed that the genetic variant of the casein kinase 1 epsilon (Csnk1ε) gene contributes to response variability to amphetamine and methamphetamine in both mice and humans. A polymorphism in the Csnk1ε gene has been reported to be associated with heroin dependence. In this study, to identify markers contributing to the genetic susceptibility of the Csnk1ε gene to heroin dependence, we examined the potential association between heroin dependence and 14 single nucleotide polymorphisms (SNPs; rs1997644, rs135764, rs867198, rs135763, rs135757, rs6001090, rs5750581, rs1534891, rs1005473, rs3890379, rs2075984, rs2075983, rs135749, and rs135745) of the Csnk1ε gene using the MassARRAY system. Participants included 398 heroin-dependent patients and 436 healthy controls from a Han Chinese population. The result revealed a strong association between the rs135745 (3′-untranslated region) genotype distribution and heroin dependence (P?=?0.0006). The frequency of the C allele was significantly higher in the heroin-dependent patients than in the healthy controls (χ²?=?7.172, P?=?0.007, OR?=?1.426, 95 % CI?=?1.099–1.849). Further genotype and clinical phenotype correlation study of the rs135745 carriers showed that the amount of heroin self-injection was higher in patients with the GC?+?CC genotype compared to the patients with the GG genotypes (P?<?0.01). Strong linkage disequilibrium (LD) was observed in block 1, block 2, and block 3 (D′?>?0.9), whereas significant evidence of LD was not observed between these SNPs in our sample population. These findings point to a role for Csnk1ε polymorphisms in heroin dependence among the Han Chinese population and may be informative for future genetic or neurobiological studies on heroin dependence.     

Polymorphisms of Transferrin gene are associated with schizophrenia in Chinese Han population

Several recent studies have provided evidence that abnormalities in oligodendrocyte and myelin function may contribute to the etiopathology of schizophrenia. Transferrin (TF), an iron transport glycoprotein playing an important role in synthesis of myelin and the development of oligodendrocytes, has been identified as down-regulated expression in schizophrenia brain by microarray, quantitative PCR and in situ hybridization method. In order to further assess the role of TF in schizophrenia, we examined seven polymorphisms in TF region using a set sample of Chinese Han subjects consisting of 326 schizophrenia patients and 344 healthy controls. Four single nucleotide polymorphisms (SNPs) namely, rs4481157, rs3811655, rs6762415 and rs1405022 were analyzed in this study. Our results showed that one intronic SNP had strong association with schizophrenia (rs3811655: allele C>G, P=1.34E-6, OR=1.89, 95% CI=1.46-2.46; genotype P=3.72E-6). Two haplotypes A-C and G-G constructed of rs4481157-rs3811655 also revealed significant associations with schizophrenia (global P=0.0001). Our findings support that TF gene may be involved in susceptibility to schizophrenia in the Chinese Han population. However, further studies are needed to confirm these findings in other populations and to identify functional variants in TF that may be implicated in pathogenesis.