Cytochrome P450 (CYP) 1A2, sulfotransferase (SULT) 1A1, and N-acetyltransferase (NAT) 2 polymorphisms and susceptibility to urothelial cancer

Purpose Arylamines are suspected to be the primary causative agent of urothelial cancer in tobacco smoke. In the human liver, arylamines are N-hydroxylated by a cytochrome P450 (CYP)1A2-catalyzed reaction, which produces a substrate for O-esterification that can be catalyzed by N-acetyltransferases (NAT) or sulfotransferases (SULT). Recently, several polymorphisms of CYP1A2, SULT1A1, and NAT2 that affect their activities have been reported.Methods In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes.Results The frequencies of NAT2 intermediate or slow acetylator genotype were significantly higher in the urothelial cancer patients than in the healthy control subjects [odds ratio (OR)=1.49, 95% confidence interval (95% CI) 1.06–2.09, OR=3.23, 95% CI 1.72–6.08, respectively]. Stratifying by amount of smoking, among subjects who consumed >33.5 pack-years and carried the SULT1A1 *1/*1 or NAT2 slow acetylator genotype, the OR was 1.73 (95% CI 1.01–2.97) whereas it was 7.31 (95% CI 1.90–28.05) in non-smokers who carried the homozygous wild genotype, respectively. The relationships between CYP1A2, SULT1A1, and NAT2 polymorphisms and clinical findings including tumor differentiation, stage, and recurrence rate were analyzed. Only associations between NAT2 genotype and pathological findings were admitted, and the higher OR of NAT2 intermediate and slow acetylator genotype was more likely to present to a low-grade tumor (G1) among heavy-smokers.Conclusions Our results suggest that SULT1A1 *1/*1 and NAT2 slow acetylator genotypes might modulate the effect of carcinogenic arylamines contained in tobacco smoke, and that the modulation of NAT2 intermediate and slow acetylator genotype has a tendency to present a higher risk for highly differentiated tumors among heavy-smokers.     

基质金属蛋白酶-2和-9在食管鳞状细胞癌中的过表达

目的 探讨人食管鳞癌组织中基质金属蛋白酶(MMP)-2、-9的表达及其临床意义.方法 采用免疫组织化学法,检测57例食管鳞癌及10例食管正常黏膜石蜡标本中MMP-2、-9蛋白的表达情况.结果 食管鳞癌组织中MMP-2及MMP-9阳性表达率(40.3%,61.4%)显著高于正常组织(0.0%,10.0%)(P＜0.05).食管鳞癌组织中MMP-2及MMP-9阳性表达与淋巴结转移和癌组织浸润深度有显著相关性(P＜0.05),而与患者的性别、年龄和组织分化程度无显著相关性(P＞0.05).结论 MMP-2和MMP-9在食管癌中显著高表达,与食管癌的转移及侵袭有关,其异常表达可能共同参与食管癌的发生、发展过程,检测MMP-2、-9可作为食管癌病理学特点的参考指标.     

Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: A meta-analysis

Objectives: The purpose of this study was to evaluate whether a single-nucleotide polymorphism (SNP) IL12B 3^′UTR +1188A/C (rs3212227) confers susceptibility to several autoimmune diseases.

Methods: A systematic literature search was conducted to identify relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association.

Results: Twenty-five studies were included in the meta-analysis, which contained 9794 cases and 11,330 controls. Our result indicated that IL12B +1188A/C (rs3212227) polymorphism was associated with type-1 diabetes (T1D) in the dominant model (p?=?0.008), and an increased risk was found in East Asians in the dominant model (p?<?0.001). East Asians rheumatoid arthritis (RA) patients seemed to be at risk of allelic model (p?=?0.011). As to Behcet's disease (BD), there was a risk in dominant model (p?=?0.020) and positive associations of dominant model, allelic model in East Asians (p?=?0.009; p?<?0.001, respectively). But we failed to find any association between IL12B +1188A/C (rs3212227) polymorphism with Graves’ disease (GD) and ankylosing spondylitis (AS).

Conclusions: The present study suggests that the IL12B +1188A/C (rs3212227) polymorphism might be associated with genetic susceptibility to autoimmune diseases, such as T1D, RA, BD, but not GD and AS.     

单核苷酸多态性与原发性肝细胞癌易感性的研究进展

人群特异的癌症遗传性与DNA序列中的多态性变异有关.人类基因组中最常见的序列变异是单个碱基的稳定替换,即单个核苷酸多态性(single nucleotide polymorphism,SNP).人体许多表型、对药物的敏感性或疾病的易感性差异等都可能与SNP相关,已有人将SNP称为第三代遗传标志.原发性肝细胞癌(HCC)某些特定的SNP可以通过改变基因的功能和表达影响个体对HCC的易感性,具体可能在多种途径发挥作用,现就能够影响HCC发病风险的SNP位点综述如下.     

NOS1基因多态性与湖北汉族人变应性哮喘易感性的关系

目的　研究一氧化氮合成酶结构式基因 (NOS1)第 2 9外显子翻译终止位点下游 2 76 bp处 C/ T(C5 2 6 6 T)位点多态性与湖北汉族人变应性哮喘易感性及血浆 Ig E水平的关系。方法　用聚合酶链反应和限制片段长度多态性 (PCR- RFL P)方法对湖北汉族 134例变应性哮喘患者 (哮喘组 )及 90例无血缘关系的汉族健康人(对照组 )进行 NOS1基因 C5 2 6 6 T位点多态性分析 ,用免疫发光法测定血浆总 Ig E水平。结果　哮喘组 NOS1基因 C5 2 6 6 T位点 TT基因型频率与对照组相比差异显著 (P=0 .0 0 9) ,T等位基因频率与对照组相比无显著性差异 (P>0 .0 5 )。哮喘组 TT基因型者血浆总 Ig E显著高于 CC和 CT基因型者 (P<0 .0 5 )。结论　 NOS1基因C5 2 6 6 T位点 TT基因型与湖北汉族人哮喘易感性和高血浆总 Ig E水平均相关。     

IgE低亲合力受体基因外显子9G/A多态性与支气管哮喘易感性

目的探讨IgE低亲和力受体基因(FcεRⅡ)外显子9是否存在G→A突变并研究其与哮喘易感性的关系。方法正常组和哮喘组各100例,抽取外周血2ml,分离血细胞并提取DNA,用聚合酶链反应限制性片段长度多态性(PCRRFLP)分析检测外显子9上的G→A碱基突变,如存在G→A突变,则用χ2检验比较哮喘组与正常组之间基因型频率与等位基因频率。结果本实验未能发现基因外显子9上存在G→A突变,聚丙烯酰胺凝胶电泳(PAGE)检测不到RFLP。结论所研究人群中到FcεRⅡ基因不存在(G→A)点多态性。     

白细胞介素-1B基因多态性分布与胃癌易感性的相关性研究

目的 研究白细胞介素-1B(IL-IB)基因多态性与胃癌间的相关性，建立本地区IL-1B基因多态性正常分布。方法 应用基因芯片测定了54例济南地区正常人群中IL-1B基因启动子区域内-31(T-C转换)和-511(C-T转换)位点多态性。结果 本组-31CC、-31CT、-31TT和-31C携带者出现的频率分别为27％、70％、3％和97％；-511CC、-511CT、-511TT和-511T携带者出现的频率分别为39％、35％、26％和60％；-31CC／-511TT基因频率(14．5％)高于-31TT／-511CC基因频率(5％)。结论 不同地区和不同种族间IL-1B-31和-511位点多态性分布存在差别，这种差别与不同地区和种族间胃癌的易感性相关。     

VEGF gene polymorphisms and susceptibility to colorectal cancer disease in Italian population

Background  The vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen involved in the process of angiogenesis, a crucial phase in tumor growth and metastasis. We carried out a case–control study to evaluate whether polymorphisms of VEGF gene modulate the risk of developing colorectal cancer disease (CCD). Materials and methods  We evaluated VEGF −2578A/C, −460T/C, and +405C/G genotypes obtained from a series of 302 CCD patients and 115 controls from the Italian population using polymerase chain reaction restriction fragment length polymorphism assay. Results  Strong linkage disequilibrium (LD) was detected between −2578A/C and −460T/C (D′ = 0.97; CI = 0.93–1) and between −2578A/C and +405C/G (D′ = 0.97; CI = 0.98–1) in the case group. Complete LD was detected between −2578A/C and +405C/G and between −460T/C and +405C/G (D′ = 1; CI = 0.84–1; CI = 0.82–1, respectively) in the control group. A reduced risk for the disease was associated with −2578C/A and −2578C/C (odds ratio (OR) = 0.34, CI = 0.162–0.676 and OR = 0.38, CI = 0.181–0.775, respectively). A direct association was found for carriers of the VEGF −460C/C polymorphism (OR = 3.55; CI = 1.659–8.469). We identified a protective haplotype −2578A, −460T, and +405G (OR = 0.04; CI = 0.009–0.19) and two different high-risk haplotypes −2578A, −460C, and +405G (OR = 1.90; CI = 1.31–2.27) and −2578C, −460C, and +405C (OR = 9.62; CI = 1.3–70.87). Conclusions  The present study suggests that the VEGF gene polymorphisms may play a role in the development of colorectal cancer. Paolo Maltese and Emanuele Canestrari contributed equally to the study.     

Cytochrome P4501A1 polymorphism is associated with susceptibility to acute lymphoblastic leukemia in adult Mexican patients

We studied the role of cytochrome P4501A1 (CYP1A1 Val/Val) genotypes in the etiology of acute lymphoblastic leukemia (ALL) in adult Mexican patients. Distributions of CYP1A1 Val/Val genotypes in peripheral blood DNA samples from 136 healthy controls and 136 adult patients with ALL were evaluated. There was an increased frequency of the CYP1A1 Val/Val genotype among ALL patients, showing a significant association between this genotype and the risk of developing ALL.     

Incidence and survival of patients with Dukes' A (stages T1 and T2) colorectal carcinoma: a 15-year population-based study

Background and aims Patients with stage I (Dukes A) colorectal carcinoma tend to show a good prognosis; however, recurrences can be observed in some patients. Through a specialized colorectal cancer Registry, we attempted to investigate the epidemiological and clinical features of individuals with Dukes A neoplasms.Patients and methods From 1984 to 1998, 295 individuals were diagnosed with Stage I /Dukes A tumors; 150 of these had lesions infiltrating the muscular wall (T2), while 145 had neoplasms limited to the submucosa (T1).Results Dukes A tumors represented 13.8% of all registered neoplasms; the percentage doubled over the study period (8.1% in the first year vs. 16.8% in the final year). In each year of observation, the preferential locations were the rectum and sigmoid colon (75% of all lesions). Most patients required surgery, but only 21.3% could be managed by endoscopic polypectomy. Overall 5-year survival was 81.0% (82.1% in T1, 80.0% in T2). Recurrences were seen in 6.8% (2.8% in T1, 10.7% in T2), while 36 patients (12.2%) died of causes unrelated to colorectal cancer. In 17 out of 20 patients who died of cancer, the lesions were localized in the rectosigmoid region. Survival analysis showed a significantly better prognosis (P<0.007) for patients with T1 tumors.Conclusions The proportion of stage I colorectal tumors tended to increase over time. Although the overall prognosis is good in four-fifths of the cases, approximately one-fifth of these patients die of recurrent disease or of other causes. As expected, the prognosis was significantly more favorable for patients with T1 lesions. For patients with T2 tumors, radical surgery is the most appropriate approach.     

核因子kappaB基因多态性与2型糖尿病易感性相关的研究

目的探讨核因子kappaB基因多态性与2型糖尿病（T2DM）易感性的相关性。方法PCR荧光法分析T2DM组（160例）和正常健康对照组（Con,82例）NF-κB的（CA）重复序列的多态性。结果A4（124bp）等位基因的频率在Con组中明显高于T2DM组;A8（132bp）等位基因频率在T2DM组中明显高于Con组。结论NF-κB1基因在T2DM易感性上可能起到重要作用：等位基因A8携带者比A4携带者更容易患T2DM。     

The -2518A/G polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene and diabetes risk: a meta-analysis

We conducted a meta-analysis to investigate the association between the −2518A/G polymorphism in the MCP-1 gene and the risk of diabetes. Ten case-control studies were included in this meta-analysis. Results indicated this polymorphism may be a risk factor for diabetes in Caucasians. Future studies are needed to validate our conclusions.     

红细胞补体受体1基因多态性与特发性肺纤维化易感性的关系

目的 探讨红细胞补体受体1(CR1)密度基因多态性及CR1基因A3650G位点多态性与特发性肺纤维化(IPF)易感性的关系,CR1的HindⅢ密度相关基因组多态性与红细胞膜上CR1数量表达水平的关系.方法 选择2009年11月至2010年12月在河北医科大学第二医院确诊为特发性肺纤维化汉族患者64例(IPF组)及54名同期河北医科大学第二医院健康汉族体检者作为健康对照组.应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)及聚合酶链反应(PCR)检测两组CR1的HindⅢ密度相关基因组多态性以及CR1基因A3650G多态位点的基因型;采用流式细胞术检测CR1在红细胞膜上的数量表达水平.结果 CR1HindⅢ密度相关基因基因型HH型、HL型和LL型在IPF组的分布频率分别为32.8％(21/64)、46.9％(30/64)和20.3％(13/64),在健康对照组分布频率分别为72.2％(39/54)、25.9％(14/54)和1.9％(1/54),差异有统计学意义(x2=15.516,P＜0.05).IPF组与健康对照组HL+ LL基因型优势比OR值为5.32(x2=18.20,P＜0.05).CR1基因A3650G位点的等位基因频率在IPF患者和健康对照组之间比较,总体分布差异无统计学意义(x2=1.094,P＞0.05).CR1在IPF组红细胞上的平均荧光强度为13.46±3.86,与健康对照组(24.33±3.84)比较,差异有统计学意义(t=15.288,P＜0.05).两组CR1基因HindⅢ-RFLP高表达型的红细胞CR1数量表达水平高于中表达型(t=9.973,P＜0.05),中表达型高于低表达型(t=4.359,P＜0.05).IPF组CR1基因HindⅢ-RFLP高表达型、中表达型、低表达型的红细胞CR1数量表达水平均低于健康对照人群(均P＜0.05).结论 红细胞CR1数量表达水平既受CR1基因HindⅢ密度相关基因组多态性遗传控制又受后天因素的影响.CR1基因HL型和LL型人群可能是特发性肺纤维化的易感人群,携带L等位基因的个体存在对特发性肺纤维化的易感性.     

HLA-DRB1和肿瘤坏死因子α基因多态性与肝硬化的遗传易感性

目的探讨HLA-DRB1和肿瘤坏死因子(TNF)α基因多态性与肝硬化遗传易感性之间的关系.方法应用聚合酶链反应-序列特异性引物法、限制性片段长度多态性等技术检测106例乙型肝炎后肝硬化患者和108例健康对照者的HLA-DRB1和TNFα基因多态性.结果肝硬化组HLA-DRB1*120X等位基因频率比对照组显著升高(35.9%比11.1%,P＜0.001),TNFα中TNF2/1基因型频率比对照组明显升高(19.8%比10.2%, P＜0.05),DRB1*150X等位基因频率明显低于对照组 (13.2%比30.6% ,P＜0.05),分层分析表明,DRB1*120X等位基因与肝硬化的关联大于TNF2等位基因.结论 HLA-DRB1*120X和TNF2等位基因与乙型肝炎后肝硬化的遗传易感性相关,携带这2个等位基因的个体发生肝硬化的危险性增加.HLA-DRB1*120X等位基因可能是肝硬化的易感基因,HLA-DRB1*150X等位基因为抗性基因.     

Genetic susceptibility and gastric cancer risk: The importance of meta-analyses as a statistical tool

Gastric cancer (GC) is a complex disease and a worldwide health burden due to its high prevalence and poor prognosis. A deeper knowledge of the factors involved in the development and progression of GC could help to identify subpopulations at risk that therefore require surveillance or early treatment strategies. Current research is based on the study of genetic variants that confer a higher risk of GC and their interactions with environmental exposure. Recently, meta-analysis has emerged as an important statistical method involving pooling of data from individual association studies to increase statistical power and obtain more conclusive results. Given the importance of chronic inflammation in the process of gastric carcinogenesis, the present article reviews the most recent meta-analyses of the contribution of cytokine gene polymorphisms to GC risk.     

Lysosomal acid lipase gene single nucleotide polymorphism and pulmonary tuberculosis susceptibility

BackgroundThe factors that predispose to pulmonary tuberculosis (PTB) are not fully understood, However. Gene polymorphisms have been associated with PTB development.ObjectivesIn this study, we investigated the relationship between LIPA gene polymorphisms and a predisposition to pulmonary tuberculosis caused by Mycobacterium tuberculosis.MethodsA total of 202 cases of PTB and 218 healthy controls (HCS) were included in this study. Analyses were done under allelic, homozygous, and heterozygous, dominant, recessive models, and were used to calculate values, odds ratios (ORs), and 95% confidence intervals (CIs) for assessing the association between single nucleotide polymorphisms (SNPs) and disease risk. Genotyping was conducted using the real time polymerase chain reaction with high resolution melting curve analysis.ResultsWhen comparing PTB patients with healthy controls (HCS), significant associations with disease development were observed for both SNPs rs1051338 and rs7922269. Analysis was done based on models of genetic inheritance in man that is co-dominant, recessive and dominant models. Rs1051338, the heterozygous (AC vs. AA) P: 0.001, OR: 1.998, 95% CI: 1.312–3.042 and homozygous (CC vs. AA) P: < 0.001, OR: 4.078, 95% CI: 2.134–7.796 Co-dominant associated with increased risk for the disease. Under recessive (CC vs. AA + AC), P: 0.001, OR: 2.829: 95% CI: 1.543–5.185 and dominant model (AC + CC vs. AA) P: < 001, OR: 2.331, 95% CI: 1.564–3.474 the genotypes distribution increased the individual risk, plus its alleles distribution (P: < 0.001, OR: 2.004, 95% CI: 1.505–2.669). Considering SNP rs7922269 mutation significantly increased pulmonary tuberculosis risk as was observed in the homozygous GG vs. TT (P: 0.003, OR: 3.162, 95% CI: 1.431–6.989); heterozygous GT vs. TT (P: < 0.001, OR: 1.2.259, 95% CI: 1.503–3.394); dominant model (GT + GG vs. TT; P: < 0.001, OR: 2.061, 95% CI: 1.402–3.032) and the allele G (P: < 0.001, OR: 1.829, 95% CI:1.361–2.458), however no significant association was observed in the Recessive model (GG vs. TT + GT; P: 0.057, OR: 2.568, 95% CI: 0.965–4.432).ConclusionThe findings of our study strengthen the hypothesis that LIPA rs1051338 and rs7922269 polymorphism associated with increased risk for pulmonary Tb in a sample of northern Chinese population.     

E选择素基因A561C多态性与2型糖尿病易感性的相关性研究

目的　探讨E选择素基因多态性在中国汉族人群中的分布及其与 2型糖尿病的关系。方法　应用PCR RFLP技术检测 110例 2型糖尿病和 115名健康对照者E选择素的基因型,以生物化学法测定他们的血糖、血脂水平。结果　E选择素基因型AA、AC频率在 2型糖尿病组和对照组分别为 0. 864、0. 136和 0. 948、0. 052;等位基因A、C频率在 2型糖尿病组和对照组分别为 0. 932、0. 068和 0. 974、0. 026。其基因型频率和等位基因频率在 2型糖尿病组和对照组比较差异均有统计学意义 (均P<0. 05)。基因型频率的相对风险分析发现,AC基因型患 2型糖尿病的风险是AA基因型 2. 868倍 (OR=2. 868, 95%CI:1. 070~7. 688)。E选择素基因型在中国汉族人群中的分布与国外报道的资料差异有统计学意义 (均P<0. 05)。结论　E选择素A561C基因多态性与 2型糖尿病的发病有相关性,C等位基因可能是 2型糖尿病的易感基因。     

遗传基因多态性与慢性阻塞性肺疾病易感性的关系研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary discrose,COPD) 由遗传易感性和环境因素相互作用而引起的一种异质性疾病.目前,虽然其确切的病因及发病机制不甚明了,但有证据表明COPD是一种多基因疾病,遗传危险因素可作为本病易感性的一个重要原因,现就较为重要的几个遗传基因多态性与COPD易感性关系综述如下.     

Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers

BACKGROUND: A common functional genetic polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158 Met) results in 3- to 4-fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes. METHODS: We studied alcohol consumption and the COMT genotype in middle-aged Finnish men (n 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes. RESULTS: Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p < 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p = 0.031). CONCLUSIONS: The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population.