人类白细胞抗原DRB1基因多态性与三氯乙烯药疹样皮炎易感性的关系

目的研究人类白细胞抗原DRB1(HLA-DRB1)基因多态性与三氯乙烯药疹样皮炎易感性的关系。方法应用聚合酶链反应产物直接测序方法,比较112例三氯乙烯药疹样皮炎病例和142例健康三氯乙烯接触工人HLA-DRB1基因第2外显子氨基酸密码子多态性及等位基因频率分布,并计算相对危险度(OR)及其95%可信区间(95%CI)。结果病例组与接触对照组HLA-DRB1等位基因频率差异有显著性,病例组DRB1*1501、*1202和*04等位基因频率显著高于对照组(分别为18.8%vs7.7%,OR=2.748,95%CI=1.587～4.761;12.5%vs6.0%,OR=2.244,95%CI=1.195～4.214;17.4%vs11.3%,OR=1.660,95%CI=1.002～2.750),而DRB1*0301、*0901、*13和*1502等位基因频率显著低于对照组(分别为0.4%vs4.6%,OR=0.093,95%CI0.012～0.720;7.6%vs13.7%,OR=0.516,95%CI=0.283～0.939;1.3%vs6.7%,OR=0.189,95%CI=0.055～0.648;2.7%vs8.5%,OR=0.298,95%CI=0.120～0.743);病例组与接触对照组间12个位点(密码子9、11、12、13、26、28、30、33、37、70、71、74)氨基酸密码子多态性分布频率差异有显著性。结论HLA-DRB1基因多态性可能是导致三氯乙烯药疹样皮炎个体易感性差异的原因之一。     

三氯乙烯药疹样皮炎代谢酶基因多态性的病例对照研究

目的 筛选三氯乙烯药疹样皮炎的易感基因。方法 比较43例病人和47例健康三氯乙烯接触工人细胞色素P450酶（CYP1A1）、谷胱甘肽S-转移酶（GSTM1、GSTP1、GSTT1）和N-乙酰基转移酶（NAT2）的基因多态性分布，并计算相对危险度，结果 NAT2基因Kpnl位点的变异可显著增加三氯乙烯皮炎的危险性；具有NAT2慢代谢基因型的个体患皮炎危险性显著高于快代谢基因型个体，未发现其它代谢酶基因多态性与三氯乙烯皮炎易感性的相关关系。结论 NAT2基因的变异可能是导致三氯乙烯皮炎个体易感性差异的原因之一。     

三氯乙烯药疹样皮炎个体易感性指标的研究

目的探索磺胺二甲嘧啶检测N-乙酰基转移酶2（NAT2）代谢分型作为三氯乙烯（TCE）药疹样皮炎的个体易感性指标,用于TCE接触劳动者上岗前职业健康检查禁忌证的筛选,减少TCE药疹样皮炎的发生概率。方法比较17例患者和52例健康TCE接触工人N-乙NAT2代谢型分布,并计算相对危险度;对NAT2慢代谢型劳动者进行行政干预,了解干预效果。结果NAT2代谢型在2组间的分布差异有统计学意义（P〈0．01）,且NAT2慢代谢型出现三氯乙烯药疹样皮炎的危险性比快代谢型高（OR=10．50;95％CI=2．644～41．695）。干预前后发病率差异有统计学意义（P〈0．05）。结论NAT2代谢分型可能是影响三氯乙烯药疹样皮炎个体易感性的重要原因,利用磺胺二甲嘧啶检测NAT2代谢分型可能可以用于三氯乙烯接触职业禁忌的筛查。     

三氯乙烯药疹样皮炎易感性与Lag-3基因的关系

目的探索三氯乙烯药疹样皮炎的易感性基因,为其危害防治提供依据。方法将病例组及对照组基因组DNA应用降落式聚合酶链反应(PCR)扩增,然后直接测序以确定Lag-3各外显子(exon 1-8)是否存在单核苷酸多态性以及Lag3-单核苷酸多态性是否与三氯乙烯药疹样皮炎发病相关。结果56例三氯乙烯药疹样皮炎患者Lag3-基因的exon1-6及exon8基因序列相当保守,与基因库(Genebank)中一致。exon7第50bp存在多态性,但此多态性可能与该病关系不大。结论三氯乙烯药疹样皮炎的易感性与Lag3-基因单核苷酸多态性可能关系不大。     

三氯乙烯药疹样皮炎免疫相关基因易感性的研究

目的了解HLA-DM基因在三氯乙烯药疹样皮炎和正常对照者中的分布情况,探索三氯乙烯药疹样皮炎的易感性基因,为其危害防治提供依据.方法将病例组及对照组基因组DNA应用降落式PCR扩增,结合限制性片断长度多态性检测方法和直接测序,确定其DMA及DMB等位基因型和基因型,比较两组之间DMA和DMB等位基因型和基因型出现频率.结果病例组HLA-DMA*0101等位基因频率明显高于对照组(71.3%,对照组为55.0%,P＜0.05);病例组HLA-DMB*0103等位基因频率明显高于对照组(P＜0.05);对照组HLA-DMA*0102-*0102纯合子比例明显高于病例组(P＜0.05);病例组HLA-DMB*0101-*0102杂合子比例明显低于对照组(P＜0.05).结论DM基因多态性可能与三氯乙烯药疹样皮炎的易感性有关.     

乙醇代谢酶基因多态与肝癌遗传易感性研究

目的探讨乙醇代谢酶基因多态与肝癌遗传易感性的关系.方法采用病例对照研究设计,应用扩增产物长度多态性分析法同时检测研究对象的ADH2和ALDH2基因型,应用聚合酶链.反应-限制性片段长度多态性分析法检测研究对象的CYP2E1基因型.结果病例组等位基因ADH2*2、ALDH2*2和CYP2E1 C2的频率分别为58.73%、14.29%和14.29%,对照组则分别为57.18%、15.23%和16.95%;病例组基因型ADH2*2/*2、ALDH2*2/*2和CYP2E1 C2/C2的频率分别为31.75%、1.58%和3.17%,对照组则分别为36.21%、1.72%和4.60%.以上3个基因的等位基因频率和基因型频率在两组的差异均无统计学意义.结论ADH2、ALDH2和CYP2E1基因多态与肝癌的遗传易感性无关.     

ADH1B与ALDH-2基因多态性与中国人群食管癌发病风险的Meta分析

目的探讨中国人乙醇脱氢酶1B(ADH1B)和乙醛脱氢酶-2(ALDH-2)的基因多态性与食管癌发病风险的关系。方法检索中外文数据库,获得有关ADH1B和ALDH-2位点的多态性与食管癌发病风险的病例-对照研究资料,对各位点以及与饮酒的交互作用进行Meta分析,得到合并的OR值及其95%CI。结果等位基因ADH1B*1和ALDH-2*2可增加食管癌的发病风险。基因型ADH1B*1/*2和ADH1B*1/*1的OR值分别为1.24(95%CI 1.10-1.41)和3.05(95%CI 1.94-4.77);基因型ALDH-2*1/*2和ALDH-2*2/*2的OR值分别为1.6(95%CI 1.01-2.03)和0.77(95%CI 0.28-2.09)。在饮酒人群中,与基因型ADH1B*2/*2相比,ADH1B*1/*2+*2/*2的OR=3.13(95%CI 2.17-4.51);与基因型ALDH-2*1/*1相比,ALDH-2*1/*2+*2/*2的OR=4.12(95%CI 1.98-8.56)。结论在中国人群中,等位基因ADH1B*1和ALDH-2*2均能增加食管癌患病的风险,且饮酒可以增加这一风险。     

CYP2E1基因PstI/RsaI多态性与三氯乙烯药疹样皮炎易感性关系研究

目的探讨CYP2E1基因PstI/RsaI多态性与三氯乙烯(TCE)药疹样皮炎易感性的关系,为TCE药疹样皮炎易感人群筛选提供线索和依据。方法采用聚合酶链反应(PCR)扩增后限制性片断长度多态性(RFLP)方法,检测64例TCE药疹样皮炎患者和58名接触对照者中CYP2E1基因PstI/RsaI识别的CYP2E1基因型,比较各种基因型在2组人群中分布情况。结果病例组CYP2E1野生基因型(C1/C1)比例(46.9%)明显高于接触对照组(17.2%),而病例组中其他2种基因型[杂合基因型(C1/C2)和突变纯合基因型(C2/C2)合并]所占比例明显低于对照组(P<0.001)。结论 CYP2E1C1/C1基因型可能是TCE药疹样皮炎的易感基因之一。     

青海藏族人群ADH3、ALDH2基因多态性及其与饮酒行为的关系

目的 了解青海藏族男性乙醇脱氢酶3(ADH3)和乙醛脱氢酶2(ALDH2)基因多态性分布及其与饮酒行为的关系.方法 采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对ADH3和ALDH2基因型进行检测;采用回顾性问卷调查研究对象的饮酒行为.结果 等位基因ADH3*2和ALDH2*2在藏族人群中的比例分别为7.79％和22.21％;不饮酒组中等位基因ALDH2*2、ADH3*1频率高于饮酒者;危险饮酒组中等位基因ALDH2*2、ADH3*1频率低于安全饮酒者.结论 ADH3、ALDH2基因与青海藏族男性人群饮酒行为有关.     

乙醇和乙醛脱氢酶基因多态与食道癌易感性

目的 研究乙醇脱氢酶2(ADH2)和乙醛脱氧酶2(ALDH2)基因多态与食道癌易感性.方法 对江苏省泰兴市221例食道癌新发病例和191名对照的饮酒习惯等因素进行调查,采用PCR和变性高效液相色谱法(DHPLC)检测ADH2和ALDH2基因型.结果 (1)与携带ALDH2 G/G基因型者相比,携带ALDH2A/A(OR=5.69,95%CI:2.51～12.18)和ALDH2 G/A(OR=1.70,95%CI:1.08～2.68)基因型者患食道癌危险性明显增加,以携带ALDH2A/A的饮酒者最为显著(OR=8.63,95%CI:2.07～35.95).(2)无论是否饮酒,携带不同ADH2基因型者之间患食道癌的风险差异均无统计学意义.(3)携带ALDH2 A/A或G/A基因型者,不论同时携带何种ADH2基因型患食道癌的风险均显著增加,且作用效应为ALDH2 A/A≥G/A.(4)与同时携带ALDH2 G/G和ADH2 A/A的不饮酒者相比,同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G的饮酒者,患食道癌危险性OR值高达8.36(95%CI:2.98～23.46).结论 饮酒及醇醛脱氢酶基因多态与食道癌的联系主要与ALDH2有关;携带ALDH2A/A和G/A者减少酒精消耗量,有助于降低患食道癌危险性.     

人类白细胞抗原DQ基因多态性与三氯乙烯药疹样皮炎易感性的关系

目的研究人类白细胞抗原DQ（HLA-DQ）基因多态性与三氯乙烯药疹样皮炎易感性的关系。方法应用聚合酶链反应产物直接测序方法,比较112例三氯乙烯药疹样皮炎病例和142例健康三氯乙烯接触工人HLA—DQA1和HLA—DQBl基因第2外显子氨基酸密码子多态性及等位基因型频率分布。结果病例组DQA1等位基因0201和060101／0602的分布频率[7．6％（17／224）和16．1％（36／224）]显著高于对照组[3．5％（10／284）和7．0％（20／284）],而病例组DQAl等位基因0103和050101／0503／0505的分布频率[5．8％（13／224）和8．9％（20／224）]显著低于对照组[10．9％（31／284）和17．3％（49／284）]。此外,病例组与对照组之间差异有统计学意义的氨基酸密码子多态性位点见于DQA1的5个密码子（25、41、52、54和69）。病例组与对照组HLA-DQB1等位基因的分布频率差异无统计学意义。结论HLA-DQA1基因多态性可能是导致三氯乙烯药疹样皮炎个体易感性差异的原因之一。     

HLA-B*1301 as a biomarker for genetic susceptibility to hypersensitivity dermatitis induced by trichloroethylene among workers in China

BACKGROUND: Trichloroethylene (TCE) is used extensively as an industrial solvent and has been recognized as one of the major environmental pollutants. To date, > 200 cases of TCE-induced hypersensitivity dermatitis among exposed workers have been reported worldwide, and TCE exposure has become one of the critical occupational health issues in Asia. OBJECTIVES: The study aimed to identify genetic susceptible biomarkers associated with the TCE-induced hypersensitivity dermatitis in genes located in the human leukocyte antigen (HLA) region. METHODS: From 1998 to 2006, 121 cases with TCE-induced hypersensitivity dermatitis and 142 tolerant controls were recruited into the population-based case-control study. We determined HLA alleles B, DRB1, DQA1, and DQB1, by sequence-based typing. p-Values were corrected for comparisons of multiple HLA alleles. In addition, we compared and analyzed the structure character of amino acid residues of HLA molecules found in participants. RESULTS: We obtained complete genotyping data of 113 cases and 142 controls. The allele HLA-B*1301 was present in 83 (73.5%) of 113 patients compared with 13 (9.2%) of 142 tolerant workers (odds ratio = 27.5; 95% confidence interval, 13.5-55.7; corrected p = 1.48 x 10(-21)). In addition, the HLA-B*44 alleles were present in 6.2% (7/113) of patients, but were absent in TCE-tolerant workers. Residue 95 shared by HLA-B*1301 and HLA-B*44 molecules formed a different pocket F than other residues. CONCLUSIONS: The allele HLA-B*1301 is strongly associated with TCE-induced hypersensitivity dermatitis among exposed workers and might be used as a biomarker to predict high risk individuals to TCE.     

Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review

Possession of the fast metabolizing alleles for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer. To examine this association, the authors undertook a Human Genome Epidemiology review on these three genes and a pooled analysis of published studies on ADH1C. The majority of Asians had the fast ADH1B*2 and ADH1C*1 alleles, while the majority of Caucasians had the slow ADH1B*1/1 and ADH1C*1/2 genotypes. The ALDH2*2 null allele was frequently observed among Asians, though it was rarely observed in other populations. In a pooled analysis of data from seven case-control studies with a total of 1,325 cases and 1,760 controls, an increased risk of head and neck cancer was not observed for the ADH1C*1/2 genotype (odds ratio = 1.00, 95% confidence interval: 0.81, 1.23) or the ADH1C*1/1 genotype (odds ratio = 1.14, 95% confidence interval: 0.92, 1.41). Increased relative risks of head and neck cancer were reported for the ADH1B*1/1 and ALDH2*1/2 genotypes in several studies. Recommendations for future studies include larger sample sizes and incorporation of relevant ADH and ALDH genes simultaneously, as well as other genes. These considerations suggest the potential for the organization of a consortium of investigators conducting studies in this field.     

Gene-environmental interactions in alcohol-related health problems--contributions of molecular biology to behavior modifications

High alcohol sensitivity among Asians is mainly due to a genetic polymorphism in the low Km aldehyde dehydrogenase (ALDH2) gene. Strong correlations between the ALDH2 genotype and alcohol sensitivity or alcohol drinking habits have been reported. Another prevalent polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) among Asians appears to modify skin flushing reactions after exposure to ethanol but does not influence alcohol drinking behavior. Both the ADH2 and ALDH2 genotypes have been significantly correlated with the risk of alcoholism. In a Japanese occupational population, a gene-environment interaction of the ALDH2 genotype and daily hassles scores for development of problem drinking behavior was observed. Habitual drinkers with the ALDH2*1/*2 genotype had higher frequencies of sister-chromatid exchange in cultured lymphocytes and higher 8-OHdG levels in polymorphonuclear leukocytes than those with the ALDH2*1/*1 genotype. Alcoholics and heavy drinkers with the ALDH2*1/*2 genotype have been shown to have significantly elevated risks for esophageal and multiple cancers in upper digestive organs than those with the ALDH2*1/*1 genotype. In Japan, bronchial asthma patients with the ALDH2*1/*2 genotype have been shown to have a significantly elevated risk for experiencing alcohol-induced asthma compared with the ALDH2*1/*1 genotype. Providing services to determine these genotypes would be of great help for each individual to make a plan for tailor-made health promotion.     

职业性三氯乙烯药疹样皮炎52例临床分析

目的探讨职业性三氯乙烯(TCE)药疹样皮炎的早期诊断和治疗经验。方法对52TCE药疹样皮炎患者的临床资料进行回顾性分析。结果发病潜伏期为5～122d,平均36.8d。住院前非正规治疗时间为3～20d,平均10.7d。总发热47例(90.4%),皮疹52例(100.0%),ALT或AST活力增高52例(100.0%),剥脱型皮炎37例(71.2%),多型红斑11例(21.2%),重型多形红斑3例(5.8%),大疱表皮松懈坏死症1例(1.9%)。痊愈49例,好转自动出院3例,治愈好转率100.0%。平均住院病程73.5d,使用糖皮质激素平均时间68.9d。结论对接触TCE者,一旦出现发热、皮疹或感冒等症状,应首先考虑到TCE药疹样皮炎的可能性。TCE药疹样皮炎除发热、皮疹外,多伴肝功能异常。早期、足量使用糖皮质激素可有效控制病情。     

Genetic factors which regulate alcohol drinking behavior and their effects on health status]

High alcohol sensitivity common among Orientals is mainly due to genetic polymorphism in the low K(m) aldehyde dehydrogenase (ALDH2) gene. The relation of the ALDH2 genotype to alcohol sensitivity and drinking behavior was investigated in a Japanese occupational population. The frequency of alcohol-associated symptoms generally increased in the order of the typical homozygote, heterozygote, and atypical homozygote. Both drinking frequency and amounts of alcohol consumption were also significantly affected by the polymorphism. Polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) appeared to contribute to skin flushing post-alcohol exposure but not to alcohol drinking behavior. Multivariate analysis revealed that high alcohol consumption, the ALDH2*1/*1 genotype, and high daily hassles levels significantly contribute to the prevalence of those with a high problem-drinking score in an occupational population. In the study to assess the effects of the ALDH2 polymorphism and alcohol use on the induction of chromosome alterations in peripheral lymphocytes, we found that lymphocytes from habitual drinkers with the atypical ALDH2 genotypes had significantly higher frequencies of sister-chromatid exchange (SCE) than those from the typical ALDH2 genotype. We also measured acetaldehyde reversibly bound to hemoglobin (HbAA). In volunteers with the ALDH2*1/*2 genotype, the HbAA levels increased immediately after the drink and the elevated levels persisted up to 48 h. Among male workers, HbAA levels were significantly correlated with the recent alcohol consumption levels in both the ALDH2*1/*1 and ALDH2*1/*2 genotypes. However, the slope was much steeper in the ALDH2*1/*2 than in the ALDH2*1/*1. SCE and HbAA may be utilized as a good biomarker for health problems in the atypical ALDH2 genotype. Further extensive studies are required for evaluation of the interactive effects of genetic and environmental factors on alcohol-related health problems.     

CYP2E1和CYP1A1及白细胞介素-4基因多态性与三氯乙烯药疹样皮炎的关系

目的 研究代谢酶基因CYP2E1和CYP1A1以及白细胞介素(IL)-4的基因多态性与三氯乙烯(TCE)药疹样皮炎易感性的关系.方法 选择35例TCE药疹样皮炎病例作为病例组,选无皮肤损害的35名健康工人作为对照组.应用实时荧光定量聚合酶链反应(PCR)和TaqMan MGB探针技术,检测病例组和对照组CYP2E1、CYP1A1和IL-4基因的单核苷酸多态性(SNP),计算病例组和对照组的基因型与等位基因型频率.结果 CYP1A1基因(rs1048943)的SNP多态性检测结果显示,病例组G等位基因频率(37.1%)明显高于对照组,差异有统计学意义(P＜0.01);检测发现,病例组CYP2E1基因-1053 C→岬位点T等位基因频率(41.4%)明显高于对照组,差异有统计学意义(P＜0.01);对IL4基因588 C→岬位点(rs2243250)检测发现,病例组TT纯合突变频率(75.0%)明显高于对照组,差异有统计学意义(P＜0.01),T等位基因频率(87.5%)明显高于对照组,差异有统计学意义(P＜0.01).结论 CYP1A1、CYP2E1和IL-4基因的某些位点的改变可能与少数TCE敏感个体对接触TCE引起的超敏反应存在密切关系,CYP1A1、CYP2E1和IL-4的基因多态性可能是TCE药疹样皮炎患者易感性差异相关的遗传学因素之一.     

Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers

AIMS: The objective was to clarify the effect of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) genotypes on the diabetic risk in Japanese workers. METHODS: At the time of mandatory health checkup, the ADH2 and ALDH2 genotypes, as well as fasting plasma glucose (FPG) levels, body mass index (BMI), smoking habit, and weekly alcohol intake, were examined in 492 men and 183 women working at motor vehicle dealerships. RESULTS: In using two-way analysis of variance to manipulate ADH2 and ALDH2 genotypes and alcohol intake (>70 g/week for men and >35 g/week for women), the FPG level after the adjustment for age, BMI, smoking habit, and another genotype was significantly higher in the men with ADH2*1/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH2*1/1 genotype. In contrast, the women with ALDH2*1/1 genotype had significantly lower FPG levels than those with the other genotypes, but there was no significant difference in the FPG level between the women with and without ADH2*1/1 genotype. Also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the women. CONCLUSIONS: These findings suggest that genotypes of ADH2 and ALDH2 can modify the diabetic risk, irrespective of amounts of alcohol consumed. Also, there may be sex differences in the effect of these enzyme genotypes on glucose metabolism.