ACE基因I/D多态与冠心病的遗传流行病学研究——表型不一致同胞对分析和传递不平衡检验

用表型不一致同胞对分析(DSP)和传递不平衡检验(TDT),在冠心病家系中探讨血管紧张素转换酶(ACE)基因内含子16中的插入/缺失(I/D)多态是否为冠心病的遗传易患因素。方法：1998年10月～1999年2月期间收集先证者一级亲属中至少有1例冠心病患者的家系45个,其中完整核心家系、父母一方、双方基因型缺失家系分别为21、2与22个,调查对象212人。PCR-RFLP方法鉴定ACE基因I/D多态性基因座基因型。条件Logistic回归进行DSP分析,TDT-STDT 1.1程序进行TDT、STDT检验。结果表明,45个冠心病家系共组成106对DSP,单变量条件Logistic回归及调整传统危险因素后的多变量条件logistic回归均未发现II、ID和DD基因型在表型不一致同胞对中的分布存在差别。对13个满足要求的核心家系进行TDT检验,杂合子父母传递给患病子代的D等位基因频率未显著偏离50％(P>0.05);24个满足要求的同胞组进行STDT检验亦未发现受累子代与非受累子代D等位基因分布有显著差异(P>0.05)。结论:在冠心病家系中未发现ACE基因I/D多态与冠心病存在关联或与疾病基因座存在连锁,说明该基因座可能不是国人冠心病的遗传易患基因。 Abstract:To investigate whether the insertion/deletion polymorphism of the human angiotensin I converting enzyme gene increased the risk of coronary heart disease (CHD) in CHD pedigrees,discordant sib pair analysis (DSP) and transmission/disequilibrium test (TDT) were used.Forty-five CHD pedigrees with at least one CHD patient in the first degree relatives of probands were recruited during Oct.1998 to Feb.1999,of which parental genotype known,one or both parental genotype missing was 21,2 and 22 respectively.ACE genotype was measured by PCR technique.Conditional Logistic regression was used to analyze the DSP,and TDT-STDT program 1.1 was used for TDT and STDT.Univariable conditional Logistic regression did not find significant difference of the distribution of three different ACE genotypes in the 106 discordant sib pairs obtained from the 45 pedigrees.After adjusting effects of traditional risk factors of CHD,no significant difference of the distribution was found by multiple Logistic regression model.Neither the TDT for 13 nuclear families or STDT(sib transmission/disequilibrium test) for 24 sibships showed significant difference between the transmitted and untransmitted ACE gene D allele distributions.Our results show that the insertion/deletion polymorphism of ACE gene is not associated or linked with CHD in Chinese population.     

海南省鼻咽癌三个高发家系报告

本文调查了鼻咽癌聚集的10个家系。在3个高发家族中,家系1两代11人中有4 人患鼻咽癌;家系2同代6人中有3人患鼻咽癌;家系3同胞5人中有3人患鼻咽癌。我们从肿瘤流行病学、病理类型及其血缘关系作了分析,认为鼻咽癌具有垂直和水平的家族发生 倾向,支持鼻咽癌有遗传倾向的看法。 Abstract:We studied the genealogy with nasopharyngeal carcinoma(NPC)and found 25 patients (18 males,7 females)with NPC in 10 families,aged from 13 to 60.The bron of the same parents were 12 patients,accounting for 48% among these patients.Both male and female patients were found in five families;the patients in four families were all male;there were all female patients in the only one family;At the sametime,21 patients with NPC were the first kinsfolk in 8 families,accounting for 84%.Besides,we looked into 3 families with high incidence;there were 4 out of 11 family members suffering from NPC in the first genealogy in 2 generations;3 of 6 brons of the same parents were ill with NPC in the third genealogy.Based on the studies of cancer epidemiology,pathology and genealogy,our results suggested that the family incidence of NPC had vertical and horizontal thndency,and that genetic factors played a decisive role in NPC incidence.     

Association Between rs1344706 of ZNF804A and Schizophrenia:A Meta-analysis

Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism（SNP） rs1344706 in the gene ZNF804 A encoding zinc finger protein 804 A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of Pub Med database identified 25 case–control studies with available genotype frequencies of rs1344706 for the meta-analysis,involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio（OR） with 95% confidence interval（CI） was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations（P = 0.028, OR = 1.138, 95% CI：1.014–1.278; P = 0.004 for heterogeneity） and Asian populations（P = 0.008, OR = 1.092, 95%CI： 1.023–1.165; P = 0.001 for heterogeneity）, but not in other populations（P = 0.286,OR = 1.209, 95% CI： 0.853–1.714, P = 0.120 for heterogeneity）. Egger’s test（P 〉 0.05） and Begg’s test（P 〉 0.05） are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.     

海南省鼻咽癌三个高发家系报告

本文调查了鼻咽癌聚集的10个家系。在3个高发家族中,家系1两代11人中有4 人患鼻咽癌;家系2同代6人中有3人患鼻咽癌;家系3同胞5人中有3人患鼻咽癌。我们从肿瘤流行病学、病理类型及其血缘关系作了分析,认为鼻咽癌具有垂直和水平的家族发生 倾向,支持鼻咽癌有遗传倾向的看法。 Abstract:We studied the genealogy with nasopharyngeal carcinoma(NPC)and found 25 patients (18 males,7 females)with NPC in 10 families,aged from 13 to 60.The bron of the same parents were 12 patients,accounting for 48% among these patients.Both male and female patients were found in five families;the patients in four families were all male;there were all female patients in the only one family;At the sametime,21 patients with NPC were the first kinsfolk in 8 families,accounting for 84%.Besides,we looked into 3 families with high incidence;there were 4 out of 11 family members suffering from NPC in the first genealogy in 2 generations;3 of 6 brons of the same parents were ill with NPC in the third genealogy.Based on the studies of cancer epidemiology,pathology and genealogy,our results suggested that the family incidence of NPC had vertical and horizontal thndency,and that genetic factors played a decisive role in NPC incidence.     

Diversity of symbiotic algae of the genus Symbiodinium in scleractinian corals of the Xisha Islands in the South China Sea

Symbiotic algae （Symbiodinium sp.） in scleractinian corals are important in understanding how coral reefs will respond to global climate change. The present paper reports on the diversity of Symbiodinium sp. in 48 scleractinian coral species from 25 genera and 10 families sampled from the Xisha Islands in the South China Sea, which were identified with the use of restriction fragment length polymorphism （RFLP） of the nuclear ribosomal DNA large subunit gene （rDNA）. The results showed that： （i） Symbiodinium Clade C was the dominant zooxanthellae in scleractinian corals in the Xisha Islands; （ii） Symbiodinium Clade D was found in the corals Montipora aequituberculata, Galaxea fascicularis, and Plerogyra sinuosa; and （iii） both Symbiodinium Clades C and D were found simultaneously in Montipora digitata, Psammocora contigua, and Galaxeafascicularis. A poor capacity for symbiosis polymorphism, as uncovered by RFLP, in the Xisha Islands indicates that the scleractinian corals have low adaptability to environmental changes. Further studies are needed to investigate zooxanthellae diversity using other molecular markers.     

Genetic analysis and gene mapping of a rice few-tillering mutant in early backcross populations (Oryza sativa L.)

A rice mutant, G069, characteristic of few tiller numbers, was found in anther culture progeny from the F1 hybrid between an indica-japonica cross, Gui630×02428. The mutant has another two major features: delayed tillering development and yellowing apex and margin on the mature leaves. As a donor parent, G069 was further backcrossed with the recurrent parent, 02428, for two turns to develop a BC2F2 population. Genetic analysis in the BC2F2 population showed that the traits of few-tillering and yellowing apex and margin on the mature leaves were controlled by one recessive gene. A pool of equally mixed genomic DNA, from few-tillering individual plants in BC2F2, was constructed to screen polymorphism with simple sequence repeat (SSR) markers in comparison with the 02428 genome. One SSR marker and three restriction fragment length polymorphism (RFLP) markers were found possibly linked with the recessive gene. By using these markers, the gene of few-tillering was mapped on chromosome 2 between RFLP marker C     

PCR-RFLP检测LDL受体基因TaqⅠ多态性位点的研究

应用聚合酶链反应(PCR)扩增人类LDL受体基因外显子4-内含子4-外显子5片段,PCR产物为1.55kb,DNA片段经序列鉴定后,进行TaqI酶切位点的RFLP分析。结果显示:中国汉族人群LDL受体基因中存在着TaqⅠ酶切位点多态性; 200个LDL受体等位基因中TaqⅠ酶切位点出现的频率为0.515,该点频率较为适中, 可作为中国汉族人群LDL受体基 因的遗传标志来进行家族性高胆固醇血症(FH)的基因诊断。所建立起的LDL受体基因TaqⅠ位点的PCR -RFLP方法具有快速、简便的特点,在FH的基因诊断上有应用价值。 Abstract:To develop rapid and sensitive technique for detectin the TaqI polymorphism at the human LDL receptor gene in Chinese,the exon4-intron4-exon5 of the human LDL receptor gene was amplified by polymerase chain reaction(PCR).The PCR products were directly analysed by restriction fragment length polymorphisms(RFLP).The results showed that the TaqI polymorphism is associated with the LDL receptor gene in Chinese of Han nationality;The frequency of T= allele (presence of TaqI cutting site)is 0.515 in 200 LDL receptor alleles.This technique may be used for rapid and sensitive screening of the LDL receptor gene for the TaqI polymorphism.     

山东胃癌高低发人群Lewis基因多态性分析

应用PCR产物直接测序的方法,检测山东省胃癌高发的临朐人群和低发的苍山人群中Lewis基因多态性T59G的分布,旨在探讨山东临朐和苍山地区胃癌发病率显著不同的内在原因,为阐明临朐地区胃癌高发的机制提供实验依据。结果表明,T59G突变个体在临朐和苍山人群中的分布频率分别为34.5%和31.6%,差别无统计学意义,P＞0.05,OR为1.14 （95% CI,0.59~2.19）。提示就此点突变而言,临朐人群和苍山人群为同一人群,具有极其相似的遗传背景;T59G不能作为区分临朐和苍山人群的遗传标志,与这两个地区胃癌发病的区别没有相关性。 Abstract:To explore the cause leading to the difference in incidence of gastric cancer between Linqu and Cangshan populations,Shandong Province,and to provide evidence for the possible mechanism of high incidence of gastric cancer in Linqu County,the distribution of T59G mutation in Lewis gene was screened between Linqu and Cangshan populations by PCR-sequencing.The frequency of individuals with T59G mutation was 34.5% in Linqu population and 31.6% in Cangshan population,respectively,with no significant difference,P＞0.05,and OR is 1.14 (95% CI,0.59~2.19).This suggests that Linqu and Cangshan populations may share the same genetic background.T59G mutation of Lewis gene could not be used as a genetic marker for Linqu and Cangshan populations and is not relevant to the difference in incidence of gastric cancer between them.     

Leber遗传性视神经病变家系的线粒体基因突变分析

为探讨Leber遗传性视神经病变（Leber′s hereditary optic neuropathy,LHON）家系线粒体DNA（mtDNA）常见致病原发突变的频谱,用聚合酶链反应（polymerase chain reaction,PCR）和单链构象多态性（single-stranded conformational polymorphism,SSCP）以及DNA测序的方法,对13个家系22位临床诊断为LHON的患者及其母系亲属21人的线粒体DNA进行检测,同时检测71例正常人作为对照。临床拟诊为LHON的13个家系中,11个家系存在mtDNA位点11778 G→A突变,另2个家系存在14484位点T→C突变。说明中国LHON病人存在线粒体DNA 11778或14484位点突变,其中14484位点突变在国内尚未见报道。 Abstract:The purpose of the study is to investigate the frequency of common pathogenic primary mitochondrial DNA mutations in pedigrees of Leber′s hereditary optic neuropathy (LHON).Mutations were determined by polymerase chain reaction (PCR),single-stranded conformational polymorphism (SSCP) and DNA sequencing.Twenty-two patients with suspicion of LHON and twenty-one their maternal relatives underwent molecular genetic evaluation.Seventy-one normal individuals underwent molecular genetic evaluation as control at the same time.Members from 13 families with suspicion of LHON,11 families had nucleotide position nt11778 G→A mutations.Another 2 families had nt14484 T→C mutations.It is concluded that the point mutations at nucleotides 11778 and 14484 are primary LHON mutations,but the point mutation of nt14484 is rare in Chinese.     

中国人群5-羟色胺2A受体基因中T102C多态性与精神分裂症的联系 Analysis of Association Between T102C Polymorphism in theSerotonin 2A Receptor Gene and Schizophrenia in Chinese Population

在研究5-羟色胺2A受体基因多态性与精神分裂症的关联分析中,调查了20 2例精神分裂症患者及202例正常对照。各相匹配组间比较未发现基因型和等位基因频率的显著性差异。结果提示,在中国人群中5-羟色胺2A受体的静态T102C突变与精神分裂症之间不存在关联。 Abstract:Association study between in the T102C polymorphism serotonin 2A receptor gene and schizoprenia was performed in 202 schizophrenics and 202 normal controls.No significant differences of genotype and allele frequencies between the matched groups were found.Our results,which are different from some other studies,excluded the association between a silent T102C change and schizophrenia in the Chinese population.     

Genetic epidemiology of schizophrenia in the population of the Tomsk region. Study of clinical polymorphism factors

The contribution of genetic, constitutional and environmental factors to the clinical polymorphism of schizophrenia was analysed. A sample from 353 pedigrees of the patients suffering from the manifest forms of schizophrenia which inhabited five districts of Tomsk region was studied using multifactorial threshold and single locus diallele models. It is established that the severity of the psychosis is mainly determined by autosomal genetic factors, the proportion of the affective disorders being specified by gonosomal factors. The type of the course of schizophrenia is closely connected with the patients' somatotype. Common environmental influences and peculiarities of personality before onset are linked with no characteristics of the clinical polymorphism studied.     

中国北方人群谷胱甘肽转硫酶P1基因多态性及其与胃癌遗传易感性的关系

为了分析中国北方人群谷胱甘肽转硫酶P1基因(glutathione-S-transferase P1, GSTP1)多态性分布, 同时探讨GSTP1基因多态性及其与幽门螺杆菌(H. pylori)既往感染联合作用对胃癌发病风险的影响, 采用多聚酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测1,612例外周血DNA GSTP1的多态性; 采用ELISA方法检测血清H. pylori IgG。结果显示, (1) 中国北方人群GSTP1基因Val等位基因分布频率为22%, 胃癌高、低发区GSTP1 Val等位基因分布频率有显著性差异(0.23/0.20); (2) 以Ile/Ile基因型为参照组与其他两种基因型比较进行胃癌的风险分析, 结果显示携带Val/Val基因型的个体患胃癌的危险性最大, 其OR为5.588 (3.256 ~ 9.591); 携带Val等位基因的个体患胃癌危险性是非携带Val等位基因个体的1.587倍; (3) 以H. pylori IgG(-)并携带GSTP1基因纯合野生型(Ile/ Ile)的个体为参照, H. pylori IgG(+)并携带纯合多态基因型(Val/Val)的个体患胃癌的风险最高, OR为17.571(6.207 ~ 49.742)。说明GSTP1 Val等位基因的分布存在人群及地区差异。携带GSTP1 Val等位基因的个体胃癌发病风险增高。GSTP1 Val等位基因纯合型与H. pylori感染对于胃癌的发生具有交互作用。     

COL9A1基因与先天性马蹄内翻足的相关性研究

应用限制性片段长度多态性技术结合测序方法,分析了84个先天性马蹄内翻足核心家系COL9A1基因内2个SNP位点rs592121与rs1135056的基因型;应用ETDT软件统计分析各SNP位点基因型与先天性马蹄内翻足的相关性;应用TRANSMIT软件构建单倍型并统计分析单倍型频率是否存在差异; 采用半定量RT-PCR方法检测25例马蹄内翻足患儿肌肉及肌腱组织COL9A1基因mRNA的表达。结果发现rs592121及rs1135056位点在先天性马蹄内翻足中均存在传递不平衡( P < 0. 05)。马蹄内翻足患儿组织中COL9A1基因表达水平高于正常组织(t = 4.7500, P < 0. 05)。提示COL9A1基因可能是先天性马蹄内翻足重要的易感基因。     

Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22

Previously, we have reported linkage of markers from chromosome 1q22 to schizophrenia, a finding supported by several independent studies. We have now examined the region of strongest linkage for evidence of linkage disequilibrium (LD) in a sample of 24 Canadian familial-schizophrenia pedigrees. Analysis of 14 microsatellites and 15 single-nucleotide polymorphisms (SNPs) from the 5.4-Mb region between D1S1653 and D1S1677 produced significant evidence (nominal P<.05) of LD between schizophrenia and 2 microsatellites and 6 SNPs. All of the markers exhibiting significant LD to schizophrenia fall within the genomic extent of the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON), making it a prime positional candidate for the schizophrenia-susceptibility locus on 1q22, although initial mutation analysis of this gene has not identified any schizophrenia-associated changes within exons. Consistent with several recently identified candidate genes for schizophrenia, CAPON is involved in signal transduction in the NMDA receptor system, highlighting the potential importance of this pathway in the etiology of schizophrenia.     

Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population

Several independent linkage studies have demonstrated that the 1q22 region is likely to harbor candidate schizophrenia susceptibility genes. Recently, some genetic variants within CAPON have been reported as exhibiting significant linkage disequilibrium to schizophrenia in Canadian familial-schizophrenia pedigrees. We examined nine single nucleotide polymorphisms (SNPs), which span an approximately 236-kb region of CAPON, in 664 schizophrenia cases and 941 controls in the Chinese Han population. We detected a significant difference in allele distributions of SNP rs348624 (P = 0.000017). Moreover, the overall frequency of haplotypes constructed from three SNPs including rs348624 showed significant difference between cases and controls (P = 0.000025). Our findings indicate that CAPON gene may be a candidate susceptibility gene for schizophrenia in Chinese Han population, and also provide further support for the potential importance of NMDAR-mediated glutamatergic transmission in the etiology of schizophrenia.     

Polymorphisms at the G72/G30 gene locus,on 13q33, are associated with bipolar disorder in two independent pedigree series

Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia.     

Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans

Catechol-O-methyltransferase (COMT) inactivates circulating catechol hormones, catechol neurotransmitters, and xenobiotic catecholamines by methylating their catechol moieties. The COMT gene has been suggested as a candidate gene for schizophrenia through linkage analyses and molecular studies of velo-cardio-facial syndrome. A coding polymorphism of the COMT gene at codon 108/158 (soluble/membrane-bound form) causing a valine to methionine substitution has been shown to influence enzyme activity, but its association with schizophrenia is inconclusive. We have screened 17 known polymorphisms of the COMT gene in 320 Korean schizophrenic patients and 379 controls to determine whether there is a positive association with a nonsynonymous single-nucleotide polymorphism (rs6267) at codon 22/72 (soluble/membrane-bound form) causing an alanine-to-serine (Ala/Ser) substitution. With the Ala/Ala genotype as a reference group, the combined genotype (Ala/Ser and Ser/Ser)-specific adjusted odds ratio was 1.82 (95% CI=1.19–2.76; P=0.005), suggesting the Ser allele as a risk allele for schizophrenia. However, the Val/Met polymorphism was not associated with an increased risk of schizophrenia in Koreans (OR=0.88, 95% CI=0.64–1.21; P=0.43). The Ala72Ser substitution was correlated with reduced COMT enzyme activity. Our results support previous reports that the COMT haplotype implicated in schizophrenia is associated with low COMT expression.     

A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

The gene encoding catechol-O-methyltransferase (COMT) is a strong candidate for schizophrenia susceptibility, owing to the role of COMT in dopamine metabolism, and the location of the gene within the deleted region in velocardiofacial syndrome, a disorder associated with high rates of schizophrenia. Recently, a highly significant association was reported between schizophrenia and a COMT haplotype in a large case-control sample (Shifman et al. 2002). In addition to a functional valine-->methionine (Val/Met) polymorphism, this haplotype included two noncoding single-nucleotide polymorphisms (SNPs) at either end of the COMT gene. Given the role of COMT in dopamine catabolism and that deletion of 22q11 (containing COMT) is associated with schizophrenia, we postulated that the susceptibility COMT haplotype is associated with low COMT expression. To test this hypothesis, we have applied quantitative measures of allele-specific expression using mRNA from human brain. We demonstrate that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia (Shifman et al. 2002) is associated with lower expression of COMT mRNA. We also show that the 3' flanking region SNP that gave greatest evidence for association with schizophrenia in that study is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Our results indicate that COMT variants other than the Val/Met change are of functional importance in human brain and that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by down-regulating COMT expression.