原发性高血压相关新基因的发现--D1S249位点与汉族EH相关联

原发性高血压(essential hypertension, EH)被认为是多基因、多因素相互作用引起的复杂疾病. 过去10年中, 高血压相关基因研究虽然已取得令人高兴的进展, 但究竟有多少基因参与发病, 及其之间的相互作用仍不清楚. 以北京房山区高血压群体及家系为研究对象, 应用全基因组扫描技术, 通过病例-对照相关研究和98对受累同胞对连锁分析, 筛查鉴定与汉族原发性高血压相关联的新基因位点. 病例-对照群体分析结果表明, 位于1号染色体长臂1q32区的D1S249微卫星多态性位点与汉族原发性高血压相关联,χ2 = 14.6, P = 0.002. 该位点存在12种等位基因, A9等位基因(181 bp)频率在高血压组较对照组明显升高, 两组间频率为13.6% v.s 2.7%, χ2 = 6.30, P = 0.01(OR = 4.57, 95% CI = 1.21～25.4); 98对受累同胞对等位基因共享连锁分析显示, χ2 = 3.78, P = 0.048. 上述结果提示, D1S249微卫星多态位点与北京房山区汉族原发性高血压遗传易感相关联, 致病基因可能于D1S249位点存在连锁不平衡.     

ABCG2基因rs2231142位点多态性与汉族女性痛风的相关性(英文)

目的:ABCG2基因第5外显子区单核苷酸多态性位点rs2231142与中国汉族男性痛风密切相关,基于痛风易感基因存在性别差异的考虑,本研究旨在探讨该单核苷酸多态性位点与中国汉族女性人群痛风易感性之间的相关性。方法:选取185例女性痛风患者和311例女性正常对照者,提取外周血基因组DNA,采用聚合酶链式反应(PCR技术),特异性扩增ABCG2基因所需要的目的片段并测序,比较痛风组和正常对照组的基因型频率及等位基因频率分布情况。结果:rs2231142位点的CC、CA、AA基因型频率在两组间存在显著差异(x2=16.519,P0.001),且痛风组中A等位基因频率显著高于正常对照组(分别为42.2%和29.3%,P0.001,OR 1.76[95%CI:1.35-2.31])。结论:ABCG2基因第五外显子区rs2231142(C/A)位点的单核苷酸多态性与中国汉族女性人群痛风易感性密切相关,携带A等位基因的汉族女性人群有更高的痛风患病率。ABCG2基因首次被证实为中国汉族女性人群的痛风致病易感基因。     

ABCG2基因rs2231142位点多态性与汉族女性痛风的相关性

目的：ABCG2基因第5外显子区单核苷酸多态性位点rs2231142与中国汉族男性痛风密切相关,基于痛风易感基因存在性别差异的考虑,本研究旨在探讨该单核苷酸多态性位点与中国汉族女性人群痛风易感性之间的相关性。方法：选取185例女性痛风患者和311例女性正常对照者,提取外周血基因组DNA,采用聚合酶链式反应（PCR技术）,特异性扩增ABCG2基因所需要的目的片段并测序,比较痛风组和正常对照组的基因型频率及等位基因频率分布情况。结果：rs2231142位点的CC、CA、AA基因型频率在两组间存在显著差异（x2=16.519,P〈0.001）,且痛风组中A等位基因频率显著高于正常对照组（分别为42.2%和29.3%,P〈0.001,OR 1.76[95%CI：1.35-2.31]）。结论：ABCG2基因第五外显子区rs2231142（C/A）位点的单核苷酸多态性与中国汉族女性人群痛风易感性密切相关,携带A等位基因的汉族女性人群有更高的痛风患病率。ABCG2基因首次被证实为中国汉族女性人群的痛风致病易感基因。     

新疆维吾尔族四个STR位点遗传多态性分析

研究新疆维吾尔族人群D16S539、D13S317、D7S820和D5S818的STR基因位点的基因及基因型分布,获得4个基因座的群体遗传学数据。采用PCR扩增技术和基因扫描技术进行样本STR遗传结构分析,并与其他种族、人群的等位基因频率进行比较。结果表明4个基因位点在新疆维吾尔族人群中均具有遗传多态性。4个基因座的基因型分布均符合Hardy-Weinberg平衡定律（P＞0.05）,不同人群基因频率分布存在一定的差异,所得到的等位基因频率等数据可为遗传学研究、法医个体畜产品识别及亲子鉴定提供依据。     

人2号染色体一个高血压病易感基因的精细定位

运用荧光标记-半自动基因扫描分型技术,在中国上海人群中对一个高血压病易感基因位点进行精细定位.结果显示:2号染色体从157.16～162.46cM这一5.3cM的范围内,出现了一个持续的LOD值高峰.该范围内所有LOD值均在2.0以上,对应P值均小于0.001.最大LOD值为2.24(P=0.00067,160.52cM).单点分析峰值在D2S151(LOD=1.86,NPL Z= 2.60).另外,有多个位点存在传递不平衡.最终,将该易感基因定位于2q14-q23(D2S151-D2S2370),这与Stoll等人用比较基因组法将大鼠数量性状位点(QTL)定位于人类基因组所得结果一致.以上结果提示,在中国上海人群中,2号染色体2q14-q23这一区域值得进一步研究.     

陕西汉族人群12号染色体上7个STR基因座的遗传多态性分析

分析了中国汉族人群中12号染色体上7个短串联重复序列（short tandem repeat,STR）基因座的多态性。 采用荧光标记基因扫描对12号染色体上D12S1718、D12S1675、D12S358、D12S367、D12S1638、D12S1646和D12S1682基因座在80名陕西咸阳、榆林汉族人中的遗传多态性进行分析。结果在中国汉族人群中, D12S1718、D12S1675、D12S358、D12S367、D12S1638、D12S1646和D12S1682基因座分别检出7、10、8、8、6、9和11个等位基因,10、17、18、18、14、18和26个基因型,杂合度分别为44.28％、66.10％、78.89％、77.89％、73.69％、74.55％和82.39％。表明这7个STR基因座在中国人群中有较好的多态性,其基因型分布均符合Hard－Weinberg平衡（P>0.05）。     

原发性肝癌染色体8p、16q 遗传变异的研究

目的:分析人肝癌(HCC)组织中染色体8p、16q部分基因及染色体片段的遗传变异及与临床病理关系,初步筛选HCC相关的抑癌基因。方法:应用聚合酶链反应-变性聚丙烯酰胺凝胶-银染法分析45例HCC组织标本中染色体8p和16q的杂合性丢失(LOH)及微卫星不稳定性(MSI)。结果:发生LOH的总频率为68.89%(31/45),其中D16S511位点的发生LOH率最高为53.33%(24/45),其次是D8S261(39.02%,16/41)和D8S499(34.88%,15/43)。MSI出现的总频率为11.11%(5/45),出现在三个微卫星位点(D8S261、D8S499及D16S511)上。结论:染色体16q23、8p22-21.3及8p12区域的LOH发生频率高,其可能存在与HCC发生发展相关的新的抑癌基因,特定位点的遗传变异可能与HBV感染、临床病理恶性程度等预后因素相关。     

CYP1A1基因单核苷酸多态性与肺癌的相关性研究

目的:探讨代谢酶CYP1A1基因MspI位点多态性与新疆汉族人群肺癌遗传易感性之间的相关性.方法:应用聚合酶链式反应(PCR)-限制性片段长度多态性(RFLP)技术检测59例新疆汉族肺癌和84例新疆汉族健康人的CYP1A1基因MspI位点多态性分布频率,并分析了CYP1A1基因MspI位点多态性与新疆汉族人群肺癌遗传易感性和患者性别之间的相关性.结果:(1)CYP1A1基因MspI位点3种多态基因型分布频率在两组间比较差异有统计学意义(χ2=6.682,P=0.035),CC基因型在病例组的分布频率显著高于正常对照组.(2)携带突变CC基因型的个体较携带TT基因型的个体患肺癌的危险性增加(OR=3.759.95%CI=1.228-11.494,P=0.035).(3)男女肺癌患者的CYP1A1基因MspI位点基因型及等位基因频率的差异均无显著性(P>0.05).结论:(1)CC突变基因型可能是新疆汉族人群的肺癌易感因素.(2)CYP1A1基因MspI位点多态性可能与新疆汉族肺癌患者的性别无关.     

原发性肝癌染色体8p、16q遗传变异的研究

目的：分析人肝癌（HCC）组织中染色体8p、16q部分基因及染色体片段的遗传变异及与临床病理关系,初步筛选HCC相关的抑癌基因。方法：应用聚合酶链反应-变性聚丙烯酰胺凝胶-银染法分析45例HCC组织标本中染色体8p和16q的杂合性丢失（LOH）及微卫星不稳定性（MSI）。结果：发生LOH的总频率为68.89%（31/45）,其中D16S511位点的发生LOH率最高为53.33%（24/45）,其次是D8S261（39.02%,16/41）和D8S499（34.88%,15/43）。MSI出现的总频率为11.11%（5/45）,出现在三个微卫星位点（D8S261、D8S499及D16S511）上。结论：染色体16q23、8p22-21.3及8p12区域的LOH发生频率高,其可能存在与HCC发生发展相关的新的抑癌基因,特定位点的遗传变异可能与HBV感染、临床病理恶性程度等预后因素相关。     

TGF-beta1 基因rs200482214 位点多态性与黑龙江省汉族人群慢性牙周炎的相关性研究

目的:探讨转移生长因子β1(transforminggrowth factor beta-l,TGF-β1)位点rs200482214基因多态性与黑龙江省汉族人群慢性牙周炎的易感性的相关性。方法:选取2012年3月至2013年7月在哈尔滨医科大学附属口腔医院牙周科就诊的135例轻、中、重度慢性牙周炎汉族患者(牙周炎组)和108例汉族健康对照者(健康对照组)作为研究对象,基因组DNA来自口腔颊粘膜拭子,采用多重单碱基延伸SNP分型技术(Multiplex SNaPshot technique)对所有受试者TGF-β1基因rs200482214位点进行检测,比较两组间此位点基因型分布和等位基因频率的差异。结果:(1)TGF-β1基因rs200482214位点各基因型(GG、GA、AA)分布均符合Hardy-Weinberg遗传平衡定律(P>0.05);(2)TGF-β1基因rs200482214位点GG、GA、AA在牙周炎组和健康对照组的分布频率分别为61.5%、30.4%、8.1%和63.0%、28.7%、8.3%,两组人群基因型分布频率差异无统计学意义(P>0.05);等位基因G、A在牙周炎组和健康对照组分布频率分别为76.7%、23.3%和77.3%、22.7%,两组人群的等位基因分布频率差异亦无统计学意义(P>0.05)。结论:TGF-β1位点rs200482214基因多态性与黑龙江省汉族人群慢性牙周炎的易感性不具有相关性。     

A Chinese Benign Adult Familial Myoclonic Epilepsy Pedigree Suggesting Linkage to Chromosome 5p15.31–p15.1

Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q23.3–q24.1, 2p11.1–q12.1, 5p15.31–p15.1, and 3q26.32–3q28, in Japanese, Italian, Thai, and French pedigrees, respectively. Recently, we investigated a Chinese BAFME family. Clinical and electrophysiological studies revealed that nine individuals were affected with BAFME. We aimed to establish the causative gene for this pedigree. We genotyped 17 microsatellite markers covering the four previously identified chromosome regions and performed linkage analyses. The linkage analysis data showed that the LOD score was 2.80 for D5S486 at no recombination. This suggested linkage to 5p15.31–p15.1 and excluded linkage to the other three loci (LOD score <0 at no recombination). Our study suggests that the causative gene responsible for BAFME in the Chinese pedigree may be located on chromosome 5p15.31–p15.1.     

Genome-wide detection of LOH in prostate cancer using human SNP microarray technology

Loss of heterozygosity (LOH) of chromosomal regions is crucial in tumor progression. In this study we assessed the potential of the Affymetrix GeneChip HuSNP mapping assay for detecting genome-wide LOH in prostate tumors. We analyzed two human prostate cell lines, P69SV40Tag (P69) and its tumorigenic subline, M12, and 11 prostate cancer cases. The M12 cells showed LOH in chromosomes 3p12.1-p22.1, 11q22.1-q24.2, 19p13.12, and 19q13.42. All of the prostate cases with informative single-nucleotide polymorphism (SNP) markers showed LOH in 1p31.2, 10q11.21, 12p13.1, 16q23.1-q23.2, 17p13.3, 17q21.31, and 21q21.2. Additionally, a high percentage of cases showed LOH at 6p25.1-p25.3 (75%), 8p22-p23.2, and 10q22.1 (70%). Several tumor suppressor genes (TSGs) have been mapped in these loci. These results demonstrate that the HuSNP mapping assay can serve as an alternative to comparative genomic hybridization for assessing genome-wide LOH and can identify chromosomal regions harboring candidate TSGs implicated in prostate cancer.     

Novel non-HLA-susceptible regions determined by meta-analysis of four genomewide scans for ankylosing spondylitis

We identified novel non-HLA-susceptible regions for ankylosing spondylitis (AS) by applying the genome-search-metaanalysis (GSMA) method to combine the previous four AS genomewide scan studies including 479 families with 1175 affected individuals. Three original genomescans were mainly analysed for Caucasian families and one analysed for Han Mongolian families. Ten bins had both Psumrnk and Pord <0.05, suggesting these bins most likely contain AS-linked loci. The 10 bins are 6.2, 16.3, 6.1, 3.3, 6.3, 16.4, 10.5, 17.1, 2.5 and 2.9. The most significant result of linkage was on chromosome 6p22.3-p21.1 (bin 6.2, Psumrnk <0.000417), where HLA loci are located. By addition of a genome scan of Chinese origin, our GSMA result further confirmed the HLA loci as the greatest susceptible region to AS and suggested that non-HLA loci chromosome 16q, 3p, 10q, 2p, 2q and 17p, may also contain AS-linked loci. The novel loci identified in our result give hints to further studies.     

Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees--263 of European ancestry (EA) and 146 of African American ancestry (AA)--together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z(lr)] threshold >/=2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.     

A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1-24.3

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant keratinization disorder with genetic heterogeneity characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, there have been three susceptible loci determined for DSAP and one locus for disseminated superficial porokeratosis (DSP), i.e. 12q23.2-24.1, 15q25.1-26.1, 1p31.3-p31.1 and 18p11.3. Moreover, the locus for porokeratosis palmaris plantaris et disseminata (PPPD) was mapped to 12q24.1-24.2, which overlapped with the first DSAP locus. Following the exclusion of these known loci in a four-generation Chinese DSAP family, we performed a genome-wide linkage analysis and identified a new locus on chromosome 16q24.1-24.3. The maximum two-point LOD score of 3.73 was obtained with the marker D16S3074 at a recombination fraction θ of 0.00. Haplotype analysis defined the critical 17.4-cM region for DSAP between D16S3091 and D16S413. This is regarded to be the forth locus for DSAP (DSAP4). ATP2C1 was sequenced as a candidate gene, however, no mutation was found. Further investigation for the genetic basis of DSAP is under way.     

Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1.

Benign adult familial myoclonic epilepsy is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course. It was recently recognized in Japanese families. In this study, we report that the gene locus is assigned to the distal long arm of chromosome 8, by linkage analysis in a large Japanese kindred with a maximum two-point LOD score of 4.31 for D8S555 at recombination fraction of 0 (maximum multipoint LOD score of 5.42 for the interval between D8S555 and D8S1779). Analyses of recombinations place the locus within an 8-cM interval, between D8S1784 and D8S1694, in which three markers, D8S1830, D8S555, and D8S1779, show no recombination with the phenotypes. Although three other epilepsy-related loci on chromosome 8q have been recognized-one on chromosome 8q13-21 (familial febrile convulsion) and two others on chromosome 8q24 (KCNQ3 and childhood absence epilepsy)-the locus assigned here is distinct from these three epilepsy-related loci. This study establishes the presence of a new epilepsy-related locus on 8q23.3-q24.11.     

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.     

在亚洲和欧洲人群中对一个AC二核苷酸重复的多态性位点与精神分裂症的关联研究

连锁研究表明, 染色体15q13~q14区域可能是精神分裂症的易感区域。在此项研究中, 使用来自中国和苏格兰的3套独立的样本, 对位于D15S118的AC二核苷酸重复的多态性位点与精神分裂症进行了关联分析。在苏格兰病例－对照样本中, 该多态性位点的等位基因在患者和正常人中的分布存在显著性差异(P = 0.04), 但是这一结果在中国的病例-对照组中没有得到重复。在中国三口之家的样本中, 我们没有观察到有等位基因从正常的父母向患病子女的传递不平衡。总之, 至少在中国人中,此结果不支持这个AC二核苷酸重复的多态性位点在精神分裂症的易感性中扮演重要的角色。后续的研究有必要进一步阐明在欧洲人中该多态性位点在精神分裂症的易感性中扮演的角色。     

A genome wide association study between copy number variation （CNV） and human height in Chinese population

Copy number variation (CNV) is a type of genetic variation which may have important roles in phenotypic variability and disease susceptibility. To hunt for genetic variants underlying human height variation, we performed a genome wide CNV association study for human height in 618 Chinese unrelated subjects using Affymetrix 500K array set. After adjusting for age and sex, we found that four CNVs at 6p21.3, 8p23.3-23.2, 9p23 and 16p12.1 were associated with human height (with borderline significant p value: 0.013, 0.011, 0.024, 0.049; respectively). However, after multiple tests correction, none of them was associated with human height. We observed that the gain of copy number (more than 2 copies) at 8p23.3-23.2 was associated with lower height (normal copy number vs. gain of copy number; 161.2 cm vs. 153.7 cm, p = 0.011), which accounted for 0.9% of height variation. Loss of copy number (less than 2 copies) at 6p21.3 was associated with 0.8% lower height (loss of copy number vs. normal copy number: 154.5 cm vs. 161.1 cm, p = 0.013). Since no important genes influencing height located in CNVs at loci of 8p23.3-23.2 and 6p21.3, the two CNVs may cause the structural rearrangements of neighbored important candidate genes, thus regulates the variation of height. Our results expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.     

Evidence for novel loci for late-onset Parkinson’s disease in a genetic isolate from the Netherlands

We studied patients with idiopathic Parkinson’s disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P=0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P-value<0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P<0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR=2.0, 95% CI 1.1–3.5, P=0.014) and D14S65 (OR=3.2, 95% CI 1.7–6.1, P<0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q.