Metabolic oxidation phenotypes as markers for susceptibility to lung cancer

That bronchial carcinoma is not an inevitable consequence of cigarette smoking has stimulated the search for host factors that might influence the susceptibility of the individual smoker. One plausible host factor would be a polymorphic gene controlling the metabolic oxidative activation of chemical carcinogens, giving rise to wide inter-subject variation in the generation of cancer-inducing and/or promoting species. Recently, three genetic polymorphisms of human metabolic oxidation have been demonstrated (as characterized by debrisoquine, mephenytoin and carbocysteine), with the metabolism of several substrates exhibiting the phenomenon. Debrisoquine 4-hydroxylation segregates into two human phenotypes, each comprising characteristic metabolic capability. We report here the frequency of debrisoquine 4-hydroxylation phenotypes in age-, sex- and smoking history-matched bronchial carcinoma and control patients. Cancer patients showed a preponderance of probable homozygous dominant extensive metabolizers (78.8%) with few recessive poor metabolizers (1.6%) compared with smoking controls (27.8% and 9.0% respectively). We conclude that the gene controlling debrisoquine 4-hydroxylation may be a host genetic determinant of susceptibility to lung cancer in smokers and that it represents a marker to assist in assessing individual risk.     

Associations between indoor environmental smoke and respiratory symptoms among preschool children in Shanghai, China

Whether indoor environmental smoke is harmful for preschool children’s respiratory health in a society where female smoking is rare has not been determined. This study is part of a cross-sectional study (CCHH study-phase one in Shanghai) and investigated associations between parental smoking and incense-burning and respiratory symptoms among 4–6 year old children in Shanghai, China. A number of 13335 valid questionnaires (response rate: 85.3%) were analyzed. A number of 56.1% (as reported by a parent) of preschool children in Shanghai are exposed to environmental tobacco smoke (ETS). A number of 40.3% of fathers and 0.9% of mothers are smokers. A number of 53.7% and 12.6% of Shanghai residents have used mosquito-repellent incense and incensation respectively. Children exposed to any parental smoking have higher prevalence of wheeze and croup than those not exposed. Current maternal smoking has a significant and positive association with wheeze (in the last 12 months, AOR, 95% CI: 1.83, 1.11–2.99). However, paternal smoking either currently or at child’s birth had only weak associations with wheeze and croup. Incense-burning (mosquito-repellent incense and incensation) had significant and negative association with doctor-diagnosed asthma (AOR, 95% CI: 0.85, 0.73–0.99) and hay fever (AOR, 95% CI: 0.80, 0.70–0.93). The results indicate that maternal smoking perhaps is a stronger risk factor for children’s respiratory health than paternal smoking.     

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.     

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.     

一类考虑吸烟群体间有效接触的时滞戒烟模型

研究一类考虑吸烟群体间有效接触的时滞戒烟模型，模型包括六个子群体：不吸烟群体、偶尔吸烟群体、习惯性吸烟群体、吸烟成瘾群体、酗烟群体和戒烟群体。以酗烟者戒烟变为戒烟者需要经历的时间周期时滞为分岔参数，讨论了Hopf分岔的存在性，并计算出模型产生Hopf分岔的时滞临界点，之后对基本再生数进行定量分析，并提出控烟参考策略。最后给出仿真示例验证了所得结果的正确性。     

一类考虑复吸的时滞戒烟模型

研究了一类考虑复吸的时滞戒烟模型，该模型包括5个子群体（潜在吸烟者、偶尔吸烟者、重度吸烟者、暂时戒烟者和永久戒烟者）.先计算出模型的基本再生数和吸烟平衡点，再以偶尔吸烟者变为重度吸烟者需要经历的时间周期时滞为分岔参数讨论了Hopf分岔的存在性，并计算出模型产生Hopf分岔的时滞临界点.     

苯乙烯-甲基丙烯酸酯吸油树脂降焦

为开发一种既能降低卷烟焦油、烟碱含量，又能对整个抽吸过程均有过滤效果的滤嘴添加剂，研究以对丙烯酸酯吸油性树脂为滤嘴添加剂的应用情况，就不同用量、不同粒径的吸油性树脂对焦油、烟碱的吸附过滤功能进行评价，实验结果表明，在滤嘴中添加140mg120～140目的吸油性树脂，焦油降低19％、烟碱降低17％、烟碱／焦油比值提高14％，80％以上的多环芳烃被滤除，且整个抽吸过程都有过滤效用，烟气的香吸味基本保持不变。     

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.     

吸烟饮酒与血压的关系研究

研究了吸烟、饮酒与血压的关系随机抽样21-60岁健康的男女性样本1522人，通过调查问卷方法对样本的性别、年龄、文化水平、吸烟状况、喝酒状况、体育锻炼状况和个人病史等进行询问．用标准方法测量样本的血压值，在统计软件SAS9．0中，利用简单相关分析分别计算吸烟，饮酒与舒张压、收缩压之间的相关系数；利用协方差分析在校正其他因素的影响后分别比较吸烟组、饮酒组与各自的对照组之间血压的差异性．相关分析表明吸烟、饮酒均与收缩压显著正相关，协方差分析表明：吸烟组和饮酒组分别与其对照组之间的收缩压存在显著差异（P〈0．0001）．吸烟和饮酒是预测高血压危险性的有效指标.     

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.     

蒙古族心血管疾病及其危险因素研究进展

大量流行病学和遗传学研究证实,冠心病、脑卒中等心脑血管疾病是由遗传因素与环境因素共同作用所致的复杂疾病。心血管疾病的重要危险因素有高血压、高血脂、高血糖、肥胖、吸烟等。这些危险因素对预测心血管疾病的发病有重要的意义。现通过查阅文献,对蒙古族心血管疾病及其危险因素研究现状进行综述,为今后进一步进行蒙古族人群心血管疾病研究提供理论依据。     

近代云南民众的鸦片种植与吸食探析

近代,鸦片在云南的种植面积不一,时而低迷,时而高涨,呈现出此起彼伏的四阶段走势,诸多因素影响其中,但行政机构对鸦片的态度和政策最为关键。种植的普遍性使得鸦片吸食蔚然成风,出现瘾民遍及各行各业、农民构成主力军、男性多于女性、由社会上层向下层民众蔓延等特征。吸食鸦片人数甚众由多方因素造成,既与当时的交际应酬及整个社会风气有关,也与个体因素有关,综合起来,便造成了吸食之风的大行其道。     

Correlation of DNA adduct levels in human lung with cigarette smoking

Lung cancer is the most common cancer in men in the United Kingdom and the second most common in women, accounting for between 25 and 40% of all cancer deaths. Cigarette smoking is widely accepted as the major cause of lung cancer and linear relationships have been established between the number of cigarettes smoked and lung cancer risk. Although approximately 50 carcinogenic chemicals have been identified in cigarette smoke, a causal link between specific compounds and lung cancer has yet to be made. Studies on cigarette smokers' urine, blood and placenta have provided indications of carcinogen exposure, and although the presence of covalently-bound adducts in human DNA provides evidence of exposure to carcinogens, there have been no reports of systematic studies on the levels of DNA adducts in human lung. We report here, using the 32P-post-labelling technique, that cigarette smokers have higher adduct levels than non-smokers, that there is a linear relationship between adduct levels and daily or lifetime cigarette consumption, and that people who have given up smoking for at least five years have adduct levels similar to those of non-smokers.     

Nicotine-induced upregulation of antioxidant protein Prx 1 in oral squamous cell carcinoma

Nicotine is a source of exogenous oxidative stress, which is associated with the pathogenesis of numerous diseases including oral squamous cell carcinoma (OSCC), whereas an antioxidant protein, peroxiredoxin 1 (Prx 1), plays an important role in the modulation of this condition. This study was to investigate the association between Prx 1 and tobacco-induced oxidative stress. The expression of Prx 1 and GST in OSCC Tca8113 cells, which were pre-treated with nicotine, was determined. In the present study, MTT assay, reactive oxygen species (ROS) assay, RT-PCR and Western blot analyses, respectively, were conducted to assess cell viability, ROS level, and expression level of Prx 1 and GST in nicotine-treated Tca8113 cells. Nuclear factor kappa B (NF- B) expression was detected by immuno-fluorescence. Our results showed the growth of Tca8113 cells was increased in a dose-dependent manner when cells were treated with nicotine at concentrations from 0.1 to 10 mol/L, but the proliferation of the cells decreased at 100 mol/L. ROS levels increased in all groups treated with nicotine at concentrations of 0.1, 1, 10, or 100 mol/L for 24h. Prx 1 and GST mRNA and protein expression were up-regulated in cells treated with nicotine for the same time at different concentrations or at the same concentration for different times (P<0.05). NF-B was translocated from cytoplasm to nucleus, the expression of NF- B was increased in nucleus. These results suggest that up-regulation of Prx1 expression appears to be associated with tobacco-induced oxidative stress, which may play an important role in the pathogenesis of OSCC.     

超高效液相色谱法测定卷烟烟气中游离态和质子化尼古丁含量

采用超高效液相色谱法(UPLC)建立了一种快速测定卷烟烟气中游离态和质子化尼古丁含量的反相离子对液相色谱法.首先对游离态和质子化的尼古丁的样品提取分离条件进行了研究,该方法的流动相为含有4mmol/L的庚烷磺酸钠盐作为离子对试剂的三氟乙酸缓冲水溶液(pH=3)与乙腈混合(体积比86∶14).线性范围为0.06～129μg/mL,相关系数是0.9999,回收率为87%～99.5%.检测下限为60ng/mL.采用该方法测定了26种商品卷烟的游离尼古丁和质子化尼古丁的含量.最后,根据所测样品卷烟中游离态烟碱的数据,并结合卷烟的实际评吸结果数据进行了方差分析和相关性分析.结果表明,游离态烟碱的含量与评吸的劲头指标具有特别显著的正相关性,与喉部刺激、鼻腔刺激、口腔刺激和干躁感4个评吸指标具有一定的负相关性,而与余味评吸指标没有相关性.     

苯并[a]芘生物标志物3-羟基苯并[a]芘研究进展

 苯并[a]芘(B[a]P)是卷烟烟气中的重要有害成分,其在人体内产生的代谢物3-羟基苯并[a]芘(3-OHB[a]P),可作为B[a]P接触生物标志物用于区分不同暴露剂量人群(如吸烟者和非吸烟者,职业暴露和普通人群)及预测可能的作用机制。本文对B[a]P的危害性、3-OHB[a]P来源及检测方法进行了综述;并从3-OHB[a]P研究存在的问题和现状出发,对其在感受烟气和普通人群中进行生物监测的应用进行了展望。     

Variants conferring risk of atrial fibrillation on chromosome 4q25

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.     

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

新城疫病毒分子生物学研究进展

新城疫是由新城疫病毒引起的极易传染的毁灭性疾病.由于该病发病急、致死率高,对养禽业的发展构成了严重威胁,所以被世界动物卫生组织（OIE）定为A类烈性传染病.本文概述了新城疫病毒的基因结构与功能及基因分型等问题.     

户外活动和维生素D的摄入量与帕金森病的风险呈负相关

研究目的：评估户外活动、维生素D的摄入与帕金森病（PD）风险关系。研究方法：收集209例新发PD病例和210名无神经退行性疾病对照人群,进行食物频率问卷调查,计算膳食维生素D摄入量并记录自我报告的问卷调查户外活动情况。利用多变量Logistic回归研究膳食维生素D摄入及户外活动与PD的相关性,并校正性别、年龄、吸烟、饮酒、教育程度和身体质量指数（BMI）变量。按户外活动时间从少到多四分位分组,校正后的比值比（OR）（95%可信区间（CI））值分别为1（参考）、0.739（0.413,1.321）、0.501（0.282,0.891）和0.437（0.241,0.795）,趋势P=0.002;按维生素D摄入量从少到多四分位分组,校正后的OR值分别为1（参考）、0.647（0.357,1.170）、0.571（0.318,1.022）和0.538（0.301,0.960）,趋势P=0.011。重要结论：表明户外活动和总的维生素D摄入量与PD呈负相关;户外活动可更显著下降PD的风险相关。