藏族人群原发性高血压易感基因全基因组关联分析

目的通过全基因组关联分析(GWAS)发现并鉴定与藏族高血压关联的遗传变异。方法结合高通量芯片分析和高效DNA混合池策略的SNP-Ma P方法,对藏族原发性高血压(EH)患者与藏族正常对照进行了全基因扫描。筛选出有显著差异的位点后,用直接测序和PCR-RFLP的方法,进行群体验证,鉴定出各个基因型和相应等位基因的频率。结果在全基因组的遗传标记中,5个标签位点的等位基因频率在患者组与对照组之间存在显著差异(P9.2×10-8)。用直接测序和PCR-RFLP的方法进行群体验证,发现rs17136827和rs1866525两个位点的基因型和等位基因频率分布在两组间均无差异;rs9865108、rs12541835和rs4547758的基因型频率和等位基因频率在两组间的差异显著,携带C等位基因个体具有较高的EH发病风险。结论证实affymetrix Human SNP芯片和高效混合池策略结合的SNP-Ma P能够有效地大范围分析人类EH易感基因。rs9865108、rs12541835和rs4547758与藏族EH易感相关。     

慢性乙型肝炎易感基因的全基因组关联研究进展

慢性乙型肝炎(chronic hepatitis B,CHB)是一种由遗传、病毒与环境因素共同导致的复杂疾病,具有高度的遗传异质性。自2009年首个CHB全基因组关联研究(genome-wide association studies,GWAS)报道以来,许多GWAS相继开展。文章首先对目前发表的CHB易感基因的GWAS结果进行汇总,发现染色体6p21.32区域中CHB易感位点最多。然而目前GWAS主要基于常见变异-常见疾病原则设计,只涉及了频率≥5%的单核苷酸多态性(single nucleotide polymorphism,SNP),没有涵盖人类基因组中重要的低频变异。同时GWAS鉴定到的最显著关联的SNP大多位于内含子、基因间区等非编码区域内,导致功能学研究无法开展。乙型肝炎病毒(hepatitis B virus,HBV)功能性受体钠离子-牛磺胆酸共转运蛋白的发现,加快了HBV感染的机制研究。同时第二代测序技术的发展为CHB易感基因的发现提供了契机。因此今后的研究应将GWAS的发现与功能学研究相结合,以逐步揭示HBV感染的遗传机制。     

全基因组关联研究的策略及面临的挑战

在人类基因组测序费用还没有足够低廉的情况下,全基因组关联研究( genome-wide association study,GWAS)仍然是复杂疾病易感基因研究的有效策略之一.在此文中,对GWAS的研究设计、遗传分析方法、多重假设检验调整方法等基本原理和面临的挑战等问题进行了系统的阐述.     

全基因组SNPs和CNVs与精神分裂症的关联分析研究

精神分裂症（SP）是典型的复杂性多基因遗传疾病,随着人类基因组测序计划的完成和基因组单倍体图谱计划的实施,应用人类基因组中数以百万计的单核苷酸多态性（SNPs）和拷贝数变异（CNVs）遗传标记对精神分裂症进行全基因组关联分析,为进一步了解控制人类SP发生的遗传特征提供了重要的线索。本文就全基因组SNPs和CNVs与精神分裂症的关联分析研究做一综述。     

DNA池焦磷酸测序法在病例-对照关联研究中的应用

目的探讨DNA池结合焦磷酸测序技术（DNA poo1ing and pyrosequencing,DNA poo1ing-PSQ）在病例-对照关联性研究中的适用性。方法利用前期获取的傣族高血压病例与健康对照样本及基因分型结果,选取有序列复杂性及频率代表性的4个SNP位点,用DNA pooling-PSQ分别对由453例傣族高血压患者及488例傣族对照构建的DNAPb~进行等位基因频率测定,所得结果与用SNaPshot逐一分型计数所得结果进行比较。结果DNA poo1ing-PSQ法对于非复杂性的中高频率SNP位点等位基因频率估计较为准确,差值在0．9％-2．7％之间,所得关联分析结果与SNaPshot法一致;但对于复杂SNPrs12046278及低频SNP rs11066280,所得频率与逐一分型法相差值较大,在11．2%-15．6％之间,位点的关联性结果也不一致。结论DNA poolinm-PS0适用干中频和高频的非复杂性SNPs关联分析．     

SNP检测技术进展与全基因组关联研究

单核苷酸多态性(Single nucleotide polymorphism, SNP)是第三代遗传标记,在基因定位、遗传疾病等研究中发挥着重要作用。随着SNP检测技术的发展,在大规模人群中研究全基因组的变异位点与复杂疾病的关系成为可能。文章系统地介绍了全基因组关联研究（Genome-wide association studies,GWA）中所采用的几种高通量SNP检测技术、原理、基因芯片及其商品信息,并对SNP技术在 GWA研究中涵待解决的问题进行了阐述。     

单核苷酸多态性检测技术进展与全基因组关联研究

单核苷酸多态性(Single nucleotide polymorphism,SNP)是第三代遗传标记,在基因定位、遗传疾病等研究中发挥着重要作用.随着SNP检测技术的发展,在大规模人群中研究全基因组的变异位点与复杂疾病的关系已经成为可能.文章系统地介绍了全基因组关联研究(whole genome association,GWA)中所采用的几种高通量的SNP检测技术、原理、基因芯片及其商品信息,并对SNP技术在GWA研究中亟待解决的问题进行了阐述.     

精神分裂症主要易感基因的研究进展

精神分裂症（schizophrenia,SCZ）是一种常见的、复杂的精神疾病,至今原因不明。一般认为该病是环境因素和遗传因素共同作用的结果。近年来的研究证实,遗传因素在SCZ发病过程中起着重要的作用。采用全基因组扫描与连锁分析、全基因组关联研究与连锁不平衡分析,已发现了一系列SCZ的易感基因,其中包括DTNBPl、COMT、DISCl和NRGl等。此文在简要介绍该病研究策略的同时．综述上述几种SCZ易感基因的研容讲展。     

快速低成本全基因组DNA测序技术

人类个体的全基因组序列信息，是最为重要的生物医学信息，是实现未来个体化医疗的基础；实现个体全基因组DNA序列的快速低成本检测，是人类基因组计划完成后又一个重要的技术挑战。对该技术当前的发展现状进行回顾和分析，预计在不长的时间内人类个体全基因组的测序成本能够降低到1万元人民币以下。     

Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies

Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10⁻³ for association and 41 had P<10⁻⁷. A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82–4.6) and median minor allele frequency=0.17 (IQR: 0.12–0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10⁻⁷ discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18–1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15–0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.     

The effect of genome-wide association scan quality control on imputation outcome for common variants

Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610 k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.     

应用连锁不平衡图谱的关联研究分析方法

目的提出一种对高通量单核苷酸多态位点(single nucleotide polymorphism,SNP)关联研究的数据分析方法。方法在160名上海地区中国人中进行754个SNP的基因型检测,分别构建病例组和对照组的连锁不平衡(linkage disequilibrium,LD)图谱,通过比较两组间染色体区域LD图谱随物理距离的变化趋势寻找与疾病相关的位点,并与传统LD分析以及SNP单点、单倍型分析进行比较。结果LD图谱的分析能判断出两组间LD存在差异的染色体区域,并且该区域SNP等位基因频率和单倍型频率在两组间分布存在统计学差异或差异趋势。结论可应用该方法对高通量SNP的关联研究进行数据分析。     

Partial aortic root remodeling for root reconstruction in patients with acute type A dissection

In the present study, we reported our experience with partial aortic root remodeling for root reconstruction in patients with acute type A dissection, which involves in non-coronary sinus and/or the right coronary sinus with just one trimmed Dacron graft. Between February 2001 and May 2010, we performed partial aortic root remode-ling in 40 patients, who underwent emergency surgical intervention. The dissected sinuses were excised leaving a 3-5 mm rim of the aortic wall from the attached aortic valve cusps. A short piece (4-5 cm) of collagen coated woven polyester vascular prosthesis was trimmed with one or two "tongues" to reconstruct the non-coronary sinus and/ or the right coronary sinus, but without using separated patches. Additional procedures were including hemi-arch replacement in 11 patients, and total arch replacement plus stent-elephant trunk in 20 patients. The mean follow-up time was 36.4±3.6 months. In-hospital mortality was only 5.0% (2/40); furthermore, 3 (8.6%) patients underwent re-operation of the aortic valve and 2 (5.7%) patients died during follow-up. At the end of follow-up, trivial or no aortic regurgitation was found in 33 patients, but mild aortic regurgitation was found in 2 patients. Our data suggest that the early and mid-term results of partial aortic root remodeling were favorable, and it restored valve durability and function. Thus, the use of technique for root reconstruction in patients with acute type A dissection should be vigorously encouraged.     

美托洛尔在主动脉夹层早期应用对其预后的观察

目的分析美托洛尔在主动脉夹层早期应用对远期预后的影响。方法即选择主动脉夹层60例,分为美托洛尔治疗组30例,对照组30例,随访3年,总结分析美托洛尔对主动脉夹层预后的影响。结果治疗组3年存活率95%,对照组3年存活率76.2%。结论在常规治疗的基础上应用美托洛尔能显著提高主动脉夹层患者的存活率。     

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Genome-wide association studies for breast cancer have identified over 40 single-nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein-protein interactions vis-à-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl-CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts.     

Surgical stent-graft implantation by open procedure for type B aortic dissection without optimal landing zone

Thoracic endovascular aortic repair (TEVAR) has been considered as a first-choice treatment for type B aortic dissection (TBAD). However, some patients that is lack of optimal landing zones (<15 mm in dissected Z₂, Z₃ or the presence of a lusorian artery) still pose significant challenges for TEVAR. We utilized a surgical stent-graft implantation in the descending aorta combined with supra-aortic vessels transposition through median sternotomy for these special TBAD patients. The short- and mid-term results showed that our procedure is a good and alternative therapy for such kind patients.     

Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma

Background Aspirin‐intolerant asthma (AIA) is a subtype of asthma induced by non‐steroidal anti‐inflammatory drugs and characterized by an aggressive mucosal inflammation of the lower airway (asthma) and the upper airways (rhinitis and nasal polyp). The lower airway lesion and the nasal polyp in AIA are postulated to have common pathogenic features involving aspirin sensitivity that would be reflected in the gene expression profile of AIA polyps. Objective This study was conducted to clarify the pathogenesis of AIA using gene expression analysis in nasal polyps, and identify genetic susceptibilities underlying AIA in a case–control association study. Methods Global gene expression of nasal polyps from nine AIA patients was examined using microarray technology in comparison with nasal polyps from five eosinophilic sinusitis (ES) patients, a related disease lacking aspirin sensitivity. Based on the AIA‐specific gene expression profile of nasal polyp, candidate genes for AIA susceptibility were selected and screened by a case–control design of 219 AIA patients, 374 non‐asthmatic control (CTR), and 282 aspirin‐tolerant asthmatic (ATA) subjects. Results One hundred and forty‐three elevated and three decreased genes were identified as AIA‐specific genes that were enriched in immune response according to Gene Ontology analysis. In addition, a k‐means‐based algorithm was applied to cluster the genes, and a subclass characteristic of AIA comprising 18 genes that were also enriched in immune response was identified. By examining the allelic associations of single nucleotide polymorphisms (SNPs) of AIA candidate genes relevant to an immune response with AIA, two SNPs, one each of INDO and IL1R2, showed significant associations with AIA (P=0.011 and 0.026 after Bonferroni's correction, respectively, in AIA vs. CTR). In AIA–ATA association analysis, modest associations of the two SNPs with AIA were observed. Conclusion These results indicate that INDO and IL1R2, which were identified from gene expression analyses of nasal polyps in AIA, represent susceptibility genes for AIA.     

管腔内支架人工血管治疗主动脉夹层

目的 探讨应用腔内支架人工血管植入治疗DeBakeyⅢ型主动脉夹层的适应症、操作技巧及并发症防治。方法 对18例DeBakeyⅢ型主动脉夹层在全麻下行腔内支架人工血管植入术，经左上肢置入造影导管造影，经股动脉导入支架人工血管植于夹层破口处封闭破裂口。结果18例共植入支架人工血管20只，2例发生内漏，均经加放一只支架人工血管封堵成功。操作成功率100％，无手术死亡。近期、中期效果良好。结论 支架人工血管植入术治疗DeBakeyⅢ型主动脉夹层具有创伤小，恢复快的特点，尤其适用于病人体质差，有合并症及外科手术禁忌的病人，近期效果良好．远期效果有待观察。