Objective To investigate the association between low-density lipoprotein receptor-related protein 5 (LRP5) variants (rs12363572 and rs4930588) and type 2 diabetes mellitus (T2DM) in Han Chinese.
Methods A total of 1842 T2DM cases (507 newly diagnosed cases and 1335 previously diagnosed cases) and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms (SNPs). Odds ratios (ORs) and 95%confidence intervals (95%CIs) were calculated to describe the strength of the association by logistic regression.
Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index (BMI), the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype TT was associated with reduced risk of T2DM (OR 0.820, 95% CI 0.732-0.919). In addition, rs12363572 was associated with BMI (P<0.001) and rs4930588 was associated with triglyceride levels (P=0.043) in 507 newly diagnosed T2DM cases but not in healthy controls.
Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.

蛋白C路径基因多态性与静脉血栓栓塞症相关性的研究进展

静脉血栓栓塞症(venous thromboembolism,VTE)主要包括深静脉血栓形成(deep venous thrombosis,DVT)和肺血栓栓塞症(pulmonary thromboembolism,PTE),是一种遗传因素与环境因素共同参与的高发病率、高病死率、高致残率及高复发率的疾病[1-3],故不断探索和明确其危险因素,对于早期识别高危患者和开展疾病预防具有重要意义.

在心血管领域β_1肾上腺素能受体基因多态性的研究进展

随着分子生物学技术的发展,β_1肾上腺素能受体(β_1-AR)基因多态性在高血压、心力衰竭(心衰)、冠心病、心律失常以及特发性扩张性心肌病等心血管领域相关疾病易感性的研究不断深入.国内外众多的科学家近年来不断公布他们有关β_1-AR基因多态性研究的新发现.

The association of gene polymorphism and susceptibility to hepatocellular carcinoma (HCC) has been widely studied in recent years. Gene mutations are closely related to HCC. Understanding and measuring the gene mutations are useful to reduce the incidence of HCC and improve its prognosis.

The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion (IVS5-121_-118 GAGT) and two single nucleotide polymor-phisms (c.1251G>T and IVS14-63C>G) were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.

C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for stroke, suggesting that widespread detection could help to prevent stroke. DNA from 70 stroke pa-tients and 70 healthy controls was extracted from saliva using a magnetic nanoparticles-based method and from blood using conventional methods. Real-time PCR results revealed that the C677T polymorphism was genotyped by PCR using DNA extracted from both saliva and blood samples. The genotype results were confirmed by gene sequencing, and results for saliva and blood samples were consistent. The mutation TT genotype frequency was significantly higher in the stroke group than in controls. Homocysteine levels were significantly higher than controls in both TT genotype groups. Therefore, this noninvasive magnetic nanoparticles-based method using saliva samples could be used to screen for the MTHFR C677T polymorphism in target populations.

Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the-607C al ele may increase ischemic stroke risk in the Han Chinese population. In the present study, we recruited 291 patients with ischemic cerebrovascular disease from the Affi-liated Hospital of Qingdao University Medical Col ege, China, and 226 healthy controls. Both pa-tients and controls were from the Han population in northern China. Immunoresonance scattering assays detected increased serum amyloid A protein, C-reactive protein, and interleukin-18 levels in ischemic cerebrovascular disease patients compared with healthy controls. Analysis of the-607C/A (rs1946518) polymorphism in the interleukin-18 gene promoter showed ischemic cerebrovascular disease patients exhibited increased frequencies of the CC genotype and C al eles than healthy controls. Genotype and al ele frequencies of the interleukin-18-137G/C (rs187238) polymorphism and the-13T/C (rs11024595) polymorphism in the 5'-flanking region of serum amyloid A, showed no significant difference between the two groups. Multivariate logistic regression analysis on the interleukin-18 promoter A/C genetic locus, for correction of age, gender, history of smoking, hyper-tension, diabetes mel itus, hypercholesteremia, and an ischemic stroke family history, showed ischemic cerebrovascular disease risk in individuals without the A al ele (C homozygotes) was 2.2-fold greater than in A al ele carriers. Overal , our findings suggest that the-13T/C (rs11024595) polymorphism in the 5′-flanking region of serum amyloid A has no correlation with ischemic cere-brovascular disease, but the C al ele of the-607C/A (rs1946518) polymorphism in the interleukin-18 promoter is a high-risk factor for ischemic cerebrovascular disease in the Han population of northern China. In addition, the A al ele is likely a protective gene for ischemic cerebrovascular disease.

OBJECTIVE: To evaluate the association of X-ray cross-complementing group 1 (XRCC1) Arg399Gln, Arg194Trp and Arg280His polymorphisms with the risk of glioma. DATA SOURCES:A systematic literature search of papers published from January 2000 to August 2012 in PubMed, Embase, China National Knowledge Infrastructure database, and Wanfang da-tabase was performed. The key words used were“glioma”,“polymorphism”, and“XRCC1 or X-ray repair cross-complementing group 1”. References cited in the retrieved articles were screened manual y to identify additional eligible studies. STUDY SELECTION: Studies were identified according to the fol owing inclusion criteria:case-control design was based on unrelated individuals;and genotype frequency was available to estimate an odds ratio (OR) and 95%confidence interval (CI). Meta-analysis was performed for the selected studies after strict screening. Dominant and recessive genetic models were used and the relationship between homozygous mutant genotype frequencies and mutant gene frequency and glioma incidence was investigated. We chose the fixed or random effect model according to the heterogeneity to calculate OR and 95%CI, and sensitivity analyses were conducted. Publication bias was examined using the inverted funnel plot and the Egger’s test using Stata 12.0 software. MAIN OUTCOME MEASURES: Association of XRCC1 Arg399Gln, Arg194Trp, and Arg280His polymorphisms with the risk of glioma, and subgroup analyses were performed according to differ-ent ethnicities of the subjects.
RESULTS:Twelve articles were included in the meta-analysis. Eleven of the articles were concerned with the Arg399Gln polymorphism and glioma onset risk. Significantly increased glioma risks were found only in the dominant model (Gln/Gln+Gln/Arg versus Arg/Arg:OR=1.26, 95%CI=1.03-1.54, P=0.02). In the subgroup analysis by ethnicity, significantly increased risk was found in Asian subjects in the recessive (OR = 1.46, 95%CI = 1.04-2.45, P = 0.03) and dominant models (OR = 1.40, 95%CI = 1.10-1.78, P =0.007), and homozygote contrast (OR=1.69, 95%CI=1.17-2.45, P=0.005), but not in Caucasian sub-jects. For association of the Arg194Trp (eight studies) and Arg280His (four studies) polymorphisms with glioma risk, the meta-analysis did not reveal a significant effect in the al ele contrast, the recessive genetic model, the dominant genetic model, or homozygote contrast. CONCLUSION: The XRCC1 Arg399Gln polymorphism may be a biomarker of glioma susceptibility, es-pecial y in Asian populations. The Arg194Trp and Arg280His polymorphisms were not associated with overal glioma risk.

Objective To determine whether interleukin-1α and 1β gene polymorphism is associated with rheumatoid arthritis disease activity and bone mineral metabolism, and whether there is any relationship between IL-1β and rheumatoid arthritis (RA) motif gene. Methods IL-1 gene polymorphisms were analyzed in 65 RA patients who met American College of Radiology (ACR) criteria and 60 controls. From genomic DNA, 2 polymorphisms in each gene for IL1α-889 and IL-1β+3953 were typed by PCR-RFLP and HLA-DRB1 allele typing was also undertaken by PCR-SSOP. Some clinical and laboratory parameters were collected. The allelic frequencies and carriage rates were compared between RA patients and controls and between patients with active and quiescent disease. Comparison was also made between IL-1 polymorphism and parameters of bone mineral metabolism and between patients with the HLA-DRB1 RA motif plus IL-1β2 and patients without the two alleles. Fisher test and the analysis of variance was used to analyze the data.Results There was no significant difference in the frequency and carriage rate of IL-1α polymorphisms between RA patients and the controls. The β2/2 genotype of IL-1β was more common in female RA patients compared with controls (P=0.001). A lower carriage rate of IL-1β2 occurred in male RA patients (P=0.001). A higher carriage rate of IL-1α2 is associated with a higher ESR (P=0.008), HAQ score (P=0.03), and vit-D3 (P<0.001), but conversely a lower SJC (p=0.002), a lower RF (P=0.002) and a lower BMD at the lumbar spine (P=0.001). A higher frequency of IL-1α1 is associated with a lower CRP value (P=0.009). An increased IL-1β2 carriage is associated with active rheumatoid disease as indicated by a higher CRP (P<0.001), ESR (P<0.001) and pain score (P=0.001) and a higher BMD at the lumbar spine (P=0.007), lower vit-D3 and. Udpd/Crea level The presence of the HLA DRB1 RA motif and IL-1β allele 2 at same time did not contribute to disease activity.Conclution Polymorphisms of the IL-β gene may affect the RA occurrence. Carriage of IL-1β2 polymorphisms is associated with more active disease in RA and the presence of both the IL-1α2 and the IL-1β1 allele in RA influences bone resorption.

基因多态性与疾病相关性的遗传分析中某些值得注意的问题

绝大多数疾病的发生发展都是遗传因素与环境因素相互作用的结果,因此近年来从遗传学角度对致病基因(单基因病)和疾病易感基因(复杂性状多基因病)进行定位、鉴定和遗传流行病学的研究逐渐成为热点,国内外刊物发表相关的论文与日俱增.本文拟对该类研究中某些值得注意的问题作一讨论,以期抛砖引玉.

The study of drug response to rosuvastatin in patients with coronary heart disease according to the gene polymorphisms of interleukins

Objective To analyze the effect of interleukin 1 beta-ILl B-511C ＞ T polymorphism on lipid-lowering effect of rosuvastatin in patients with coronary heart disease (CHD) combined with acute respiratory viral infection (ARVI).Methods Lipid spectrum,concentrations of C-reactive protein and interleukin 1 beta were analyzed,genotyping of IL-1 beta ILl B-511C ＞ T polymorphism (rs16944) using polymerase chain reaction was provided in 119 patients with CHD combined with ARVI,and in control group of 313 patients suffering from CHD without viral infection from Kursk region.Results Statistically significant increase in total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels was determined in patients with CHD combined with ARVI.The effectiveness of TC and LDL-C reduction using rosuvastatin was less pronounced in this group in comparison with patients without ARVI.Conclusion Comparative analysis of the frequencies of alleles in the genotype of interleukin 1 beta-ILl B-511C ＞ T in patients with CHD combined with ARVI and with CHD without ARVI,reveals no differences.

非酒精性脂肪性肝病基因多态性

非酒精性脂肪性肝病(NAFLD)是一种遗传-环境-代谢应激相关且无过量饮酒史的临床病理综合征,疾病谱包括单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、NASH相关肝硬化甚至肝癌.

2型糖尿病患者脂蛋白脂酶基因多态性与冠心病关系的研究

高甘油三酯(TG)血症是2型糖尿病(DM)常见并发症,而且是其并发冠心病(CHD)的独立危险因子,其机制尚未阐明.本研究旨在探索2型DM患者脂蛋白脂酶(LPL)基因多态性与血脂及CHD的关系.一、对象和方法1.对象:2型DM患者216例(2型DM组),年龄(58±12)岁(40～89岁),男114例,女102例;77例并发CHD(伴CHD组),年龄(59±11)岁,男40例,女37例;139例不伴CHD(不伴CHD组),年龄(57±14)岁;正常人63例作为对照.

内皮细胞型一氧化氮合酶基因多态性与糖尿病肾病的相关性

糖尿病肾病是糖尿病(DM)致死致残的主要原因之一.近年来流行病学调查显示,有些DM患者虽血糖长期控制不良,但并不发生DN,而有些患者虽代谢控制良好,终仍发生DN[1,2],提示遗传因素在DN的发生发展中可能起关键作用.分子水平的研究发现,内皮细胞型一氧化氮合酶(eNOS)基因第7外显子的Glu298Asp(894G→T)基因点突变及第4内含子一个27bp的插入/缺失(a/b)多态与糖尿病微血管并发症及冠心病、心肌梗死的发生有明显相关性[1-5],但该点突变及多态与糖尿病肾病的相关性各家报道不一[6,7],特别是该突变及多态存在于同一个体时与DN的关系国内外尚未见报道,本文对此进行研究.

沙眼衣原体泌尿生殖道慢性持续感染患者人白细胞抗原DQA1基因多态性研究

目的 探讨人白细胞抗原DQA1 (HLA-DQA1)等位基因多态性与沙眼衣原体泌尿生殖道慢性持续性感染的相关性.方法 PCR和基因测序方法,对80例沙眼衣原体泌尿生殖道慢性持续感染患者、80例沙眼衣原体泌尿生殖道一般感染患者及80例正常人的HLA-DQA1等位基因进行检测.结果 HLA-DQA1*0102和DQA1*0501在沙眼衣原体泌尿生殖道慢性持续感染患者中的基因频率分别为22.5％、5.0％,在一般感染组的基因频率分别为5％、20％,而在正常人对照组的基因频率分别为2.5％、17.5％.沙眼衣原体泌尿生殖道慢性持续感染患者的HLA-DQA1*0102等位基因较一般感染组及正常人对照组增高,差异有统计学意义(x2=14.6286,P＜0.01)；而HLA-DQA1 *0501等位基因在持续感染患者中下降,差异有统计学意义(x2=6.2598,P＜0.05).结论 HLA-DQA1 *0102可能是沙眼衣原体泌尿生殖道慢性持续感染的易感基因或与易感基因相连锁.HLA-DQA1*0501等位基因可能具有阻止发生沙眼衣原体泌尿生殖道慢性持续感染的作用.

原发性高血压候选基因多态性的分子流行病学研究进展

原发性高血压(EH)是遗传物质与环境因素共同作用的多基因遗传性疾病,发病机制尚不明确.遗传流行病学研究表明:人群中个体血压水平的差异30%～70%归因于遗传因素,遗传背景是EH发病的重要原因.随着人类基因组单核苷酸多态性检测和分型技术的不断完善,近年来人们广泛开展EH候选基因多态性研究,以阐明EH的关键基因,从分子水平来认识其发病机制.本文主要针对近几年来研究的一些热点基因及多态性成果予以综述.

脂代谢紊乱与基因多态性研究进展

人类进化过程中受环境、种族、性别等外部条件的影响,基因(或DNA分子)的碱基序列可发生突变,存在基因多态性,所表达产物结构功能和数量改变将影响相关物质的代谢.由于脂类代谢过程需多种蛋白质共同参与,协同作用.

ACE基因多态性在心血管疾病中的作用

血管紧张素Ⅰ转化酶(ACE)是肾素血管紧张素醛固酮系统(RAAS)的重要成分,在血管张力的调节和血管平滑肌细胞的增生中起重要作用,直接影响动脉粥样硬化过程[1].血液中ACE水平与ACE基因有密切关系,ACE基因多态性可能是冠心病、心肌病、高血压等多种心血管疾病发病的独立危险因素.

中国人群中 CD40基因多态性 rs1883832与急性冠状动脉综合征相关性的研究

本刊编委,武汉大学人民医院汪明等在《DNA and Cell Biology》(2011,Vol30,no.3,IF：2.072)发表了题为"The CD40 gene polymorphism rs1883832 is associated with risk of acute coronary syndrome in a Chinese case-control study"的研究论文,主要内容如下。

细胞因子基因多态性与器官移植的关系研究进展

细胞因子和器官移植关系密切，因为外来抗原的刺激正是通过细胞因子介导而使免疫相关细胞活化，而这些活化了的细胞也正是通过细胞因子的介导才发挥了效应，导致了排斥反应。所以，凡是影响细胞因子水平的因素都有可能影响器官移植的结局。迄今为止的许多研究都表明，个体间细胞因子量存在着很大的差异，如γ干扰素（IFN-γ）和白细胞介素10 （IL-10），高表达者和低表达者间的差异可达10倍［1］。作为细胞因子，前者是促进炎症过程的，而后者则是抵抗炎症过程的。因为排斥反应的本质其实是由一种特殊的因子启动的炎症过程，所以移植受者个体间不同细胞因子水平很可能会对移植物产生不同的影响。为了找到实证依据，许多学者开展了深入的研究。迄今，国际上以英国曼彻斯特大学分子生物学中心的Hutchinson教授领导的研究小组所取得的成绩为突出，他们相继发表了多篇论文。 一、细胞因子基因多态性对细胞因子产量的调节作用 细胞因子基因多态性对细胞因子产量的调节主要通过两条途径，即转录水平的调节和翻译水平的调节。 在转录水平上，基因上游区内，特别是启动子/增强子内DNA序列的不同，即使是一个核苷酸的突变、插入或丢失，就可能显著地改变转录因子和它的结合能力和/或结合方式，从而影响转录，终表现为细胞因子水平的明显差异。据报道，IL-10基因序列－1082位点（即第一个被转录的核苷酸上游第1082个核苷酸，A、G、C及T分别指腺嘌呤脱氧核苷酸、鸟嘌呤脱氧核苷酸、胞嘧啶脱氧核苷酸及胸腺嘧啶脱氧核苷酸）G/A的变换，会直接影响转录因子EtsY与该序列DNA的结合［2］。该位点若是G，因其能结合EtsY，促进转录，因而I L-10的产量很高；若是A，因其不能很好地结合EtsY，IL-10的产量就较低。另外，如肿瘤坏死因子α（TNF-α）基因启动子上－308位点的突变，也影响IL-10的产量，该位点是G 时的IL-10水平是该位点为A时的6～7倍［3］。另有一种较特殊的基因多态性影响着细胞因子的表达，即微卫星基因多态性（microsatellite gene polymorphism）。微卫星基因广泛存在于真核细胞基因组内，它是指那些在基因非编码区域内存在的多次重复的短核苷酸序列，如GAGAGAGAGAGA……。许多研究表明，这些序列重复次数的不同，即微卫星基因多态性，会明显地影响细胞因子的水平［4-6］。 在翻译水平上，一定的基因多态性首先影响功能蛋白质的信号肽（穿膜蛋白），后者再影响功能蛋白质的含量和/或活性。这在下面细胞因子和慢性排斥关系的部分中将作更详细说明。 二、细胞因子基因多态性与器官移植急性排斥反应的关系 关于细胞因子基因多态性和器官移植急性排斥反应的关系，研究得多的是TNF-α和IL-1 0。IL-10的基因多态性与自身免疫病、炎性反应、移植后排斥反应相关。对于移植来说，拥有低水平的IL-10 基因型的受者，肾脏、心脏移植后，更易发生急性排斥反应［4,6-8］。更为重要的是，若受者同时表现为TNF-α高水平基因型和IL- 10 低水平基因型，那么发生急性排斥反应的机会就更多。TNF-α是一种强烈的直接的炎性细胞因子，而IL-10是抗炎细胞因子，高水平的TNF-α若没有足够的IL-10来对抗，则发生排斥反应的概率就增加。但近Sankaran等［9］的报道却发现，TNF-α高表达合并IL-1 0高表达时，急性排斥反应发生次数多，程度严重，预后差；而TNF-α低表达合并IL-10 低表达时，移植物受保护。为何产生不同结果，可能和各研究组的样本数还不够大有关，因为细胞因子基因多态性的分析牵涉到等位基因的频率分布，若样本数不够大，有时可得出不同的结果。另外，等位基因多态性在不同的人群和人种中可以有不同的分布。除TNF-α和I L-10基因多态性外，近，Awad等［5］发现，人类IFN-γ基因第一内含子上可有不同长度的CA重复单位，当含有#2类长度的重复序列时，移植肺非常易于发展成肺纤维化（活检证实）。 以上述及的都是宿主抗移植物的排斥反应，事实上，细胞因子基因多态性也和移植物抗宿主反应相关。Middleton等［8］完成的HLA相同的同胞间的骨髓移植的研究表明， TNF-α微卫星基因多态性D3型与严重的移植物抗宿主病（GVHD）的发生概率明显相关。同时，IL-10基因－1064位点附近处CA重复次数的多少，也和GVHD的程度密切相关。但是研究未发现通常很有意义的－308位点的基因多态性和GVHD的相关性。近Cavet等［4 ］对HLA相配的同胞间骨髓移植的研究也支持上述结论。