Searching for susceptibility genes in schizophrenia

The existence of an important genetic contribution to the aetiology of schizophrenia is well established from genetic epidemiological studies. However, the mode of transmission is complex and non-Mendelian. The main approaches used to identify susceptibility genes are linkage and association studies and the study of cytogenetic abnormalities associated with or linked to schizophrenia. Many linkage studies have been reported but have failed as yet to produce unequivocal, replicated demonstrations of linkage. However, modest evidence for several regions has been reported in more than one data set. Areas implicated include chromosome 22q11-12, 6p24-22, 6q, 8p22-21, 13q14.1-q32 and 1q21-q22, but in every case there are positive as well as negative findings. Most candidate gene studies have been based upon neuropharmacological studies suggesting that abnormalities in monoamine neurotransmission play a role in the aetiology of schizophrenia. Overall, the results have been disappointing, but it should be noted that the sample sizes in many of the older studies would now generally be regarded as inadequate. Finally, recent work has suggested that velo-cardio-facial syndrome (VCFS) is associated with rates of psychosis possibly as high as 30%. VCFS is caused by small interstitial deletions of chromosome 22q11 in 80-85% of individuals. Work is now under way to try and identify whether a gene or genes within the deleted region are of more general relevance to schizophrenia. Future directions in schizophrenia research include collecting larger samples to increase power of findings and applying novel methods for large-scale genotyping of single-nucleotide polymorphisms.     

Modeling the activation of tobacco smoking expectancies in memory in relation to use patterns

Methodology that has led to successful strategies to reduce alcohol use was applied to tobacco smoking expectancies. Individual differences scaling was used to empirically model a semantic network of associations stored in memory and preference mapping was used to model likely paths of expectancy activation for groups with different smoking histories. Smokers emphasized an external appearance-internal experience dimension and were more likely to activate expectancies of negative affect reduction. Nonsmokers emphasized a positive-negative dimension and were more likely to activate expectancies of health risks and reduced physical attractiveness. Proportionate frequencies of first associates' validated findings of the MDS-based solutions. Future efforts to alter likely activation patterns may successfully reduce the onset of smoking, enhance quit rates, and reduce relapse.     

Polymorphisms in CYP2C8 and CYP3A5 genes in the Nigerian population

Polymorphisms in CYP2C8 and CYP3A5 genes have implications for responses elicited by the ingestion of some xenobiotics, the metabolism of which are mediated by these enzymes. CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A5*6 and CYP3A5*7 are a few functionally-relevant variants of these genes which this study provides data for, in the Nigerian population. Blood samples were processed for genomic DNA from 178 unrelated subjects spread across Nigerian ethnicities and screened for these polymorphism through the Sequenom iPLEX MassARRAY platform. Results obtained were further validated with Sanger sequencing of a few samples and thereafter, the genotype data were statistically processed. All alleles were in Hardy–Weinberg equilibrium and CYP2C8*2 occurred at a frequency (95% CI) of 0.194 (0.154, 0.239), while CYP3A5*3, CYP3A5*6 and CYP3A5*7 were found at frequencies (95% CI) of 0.160 (0.124, 0.202), 0.096 (0.067, 0.131) and 0.126 (0.094, 0.166), respectively. However, CYP2C8*3 was not detected in the population. The study observed a 60% prevalence of carriers of at least a CYP3A5 polymorphism in the population, suggesting the probable existence of huge variability in CYP3A5 activity which may prove significant in the administration of drugs with narrow therapeutic windows and whose metabolism is largely mediated by CYP3A5.     

谷胱甘肽硫转移酶M1基因多态与肺癌易感性的关系

目的探讨谷胱甘肽硫转移酶M1（GSTM1）基因多态与支气管肺癌癌变的关系。方法采用回顾性“病例—对照”设计和限制性片段多态检测法（PCR—RFLP）,检测肺癌病例组103例和正常对照组138例的G卯Ml基因多态,以非条件性logistic回归模型分别对年龄、性别进行校正后计算比数比（OR）及95％可信区间（CI）。结果GSTM1的缺陷型基因（D）频率在对照组、肺癌组分别为44.2％和61．2％。logistic回归分析表明．GSTMl缺陷型（D）患肺癌的危险度升高2．09倍,差异有统计学意义。GSTM1（D）可显著增加鳞癌和小细胞癌的患病危险度。结论GSTM1（D）是患肺癌的危险因素,GSTM1（D）存在与吸烟有协同作用。     

Interest in treatments to stop smoking

We surveyed 884 Vermont (VT) tobacco smokers by random digit dialing to determine past and future use of treatment. Among those who had recently attempted to quit, 61% had ever used a treatment, 21% had ever used a psychosocial treatment, and 57% had used a medication. Among those who planned to quit in the next month, 68% stated they would use a treatment, 35% would use a psychosocial treatment, and 62% would use a medication. The major predictors of past or future use of treatment were greater cigarettes per day, older age, being a woman, and seeing a health professional. Although this survey suggests many smokers have used or plan to use a smoking cessation treatment, program data indicate less than 10% of VT smokers who try to quit use the state quitline, counseling, or free medication provision. Why smokers do not use these treatments needs to be determined.     

Age at menarche and weight concerns in relation to smoking trajectory and dependence among adolescent girls enrolled in a smoking cessation trial

Many girls adopt dieting and other practices (i.e. cigarette smoking) to control weight during puberty. This analysis explored the relationship between age at menarche and onset of daily smoking, and whether this relationship was influenced by weight concerns among treatment seeking female adolescents. The sample consisted of 71 participants enrolled in a smoking cessation trial (age 15.2 ± 1.3 years; 74.7% European American, baseline BMI 24.7 ± 5.4, age at menarche 11.7 ± 1.3 years, Fagerström Test for Nicotine Dependence score 7.0 ± 1.2). Over 60% of participants reported weight concerns at baseline, based on responses to the Eating Disorders module from the Diagnostic Interview for Children and Adolescents. Linear regression analyses revealed a significant association between age at menarche and age of onset of daily smoking (β = 0.18 ± 0.09, p = 0.038). Having weight concerns did not modify the relationships between age at menarche and smoking trajectory/severity or abstinence. Findings support previous research showing that early maturation represents a risk factor for substance use. Further study in larger samples that include non-treatment-seeking adolescent female smokers is warranted.     

贵州苗族19个STR基因座遗传多态性研究

目的 调查19个常染色体STR基因座在贵州苗族人群中的等位基因分布,评估其在法医学中的应用价值.方法 应用GoldeneyeTM20A试剂盒对226名贵州苗族健康无关个体19个常染色体STR,用310型遗传分析仪进行毛细管电泳,GeneMapper进行基因分型.结果 得到19个常染色体STR基因座等位基因的频率分布与相关法医学参数,He值0.615 0～0.915 9,DP值0.752 1～0.982 1,PE值0.309 3～0.828 1,PIC值0.521 8～0.901 2,累计个体识别率是1-1.971 6×10-22,累计非父排除概率为0.999 999 95.结论 D19S433等19个常染色体STR基因座在贵州苗族人群中具有良好的遗传多态性,对民族群体遗传学和法医物证学研究极其有价值.     

Interaction of cadmium,zinc and copper in relation to smoking habit,age and histopathological findings in human kidney cortex

In this study the concentrations of cadmium, zinc and copper were determined by atomic absorption spectrophotometry in 51 post mortem kidney cortex samples. A histopathological examination of the kidney was also performed. These parameters, together with age and smoking habit, were statistically related by means of factor analysis. The results show that the first factor associated smoking habit, cadmium and zinc and the second factor histopathological findings and age.     

Predictors of the participation of smoking parents in a proactive telephone-based smoking cessation program

OBJECTIVE: The objective of this study is to identify the predictors of participation by smoking parents in a proactive telephone-based smoking cessation program. METHODS: The smoking parents of young children from a birth cohort were interviewed and invited to take part in a telephone-based smoking cessation program. The characteristics of the parents and the predictors of participation were analyzed by chi-square test and by logistic regression. RESULTS: A total of 952 (82.9%) out of the 1149 smoking parents who were interviewed agreed to participate in the smoking cessation program. The analysis showed that the predictors of participation in a pro-active smoking cessation program are being from a middle-income household, being currently employed, having recently had a medical consultation or been hospitalized, being at the stage of contemplating a change in behavior, and perceiving the importance of quitting smoking. CONCLUSIONS: Recruitment approaches should be refined according to the identified factors to target those who might decline an invitation to participate in a smoking cessation program.     

Clinical phenotypes related to smoking cessation

Introduction

The aim of the current study is the identification of clinical phenotypes of patients visiting a specialized smoking cessation center and the determination of smoking cessation rate for each phenotype, 1 year after the initial evaluation.

Methods

Seven hundred eighty-three smokers who visited the outpatient clinic were included in the study. Demographic data, smoking habits, tobacco dependence and comorbidities were recorded. Smoking cessation rates and carbon monoxide levels were determined 1 year after the initial evaluation.

Results

Τhe overall smoking cessation rate 1 year after the initial evaluation was 32.3%. Four distinct phenotypes were identified. The first one included mainly young women with low tobacco dependence and allergic profile. The second and the third ones included mainly men with high tobacco dependence, without comorbidities, treated with varenicline and bupropione SR, respectively. The fourth one included mainly older men with high tobacco dependence and smoking related comorbidities. Smoking cessation rates for each phenotype were 33.8, 39.4, 23.3, and 24.6%, respectively.

Conclusion

Patients visiting a specialized smoking cessation center can be categorized in different phenotypes. Phenotyping may lead to a more personalized approach concerning smoking cessation.     

候选基因单核苷酸多态性与胸主动脉夹层的遗传易感性分析

目的 探讨6个候选基因单核苷酸多态性位点与中国汉族人群胸主动脉夹层发病的相关性.方法 选取中国汉族人群的206例高血压合并胸主动脉夹层患者及180例原发性高血压病患者,收集样本外周血白细胞提取DNA,利用基质辅助激光解吸电离质谱方法对5个与甲硫氨酸代谢相关基因(RS819146、RS8003379、RS2853523、RS326118与RS3788205)及1个与细胞周期蛋白依赖酶抑制剂基因相关的单核苷酸多态性位点(RS1075727)进行基因分型.比较胸主动脉夹层组与高血压组之间基因多态性位点的基因型、等位基因频率.结果 胸主动脉夹层者组的男性比例要高于高血压组.RS819146、RS8003379、RS2853523、RS326118与RS3788205基因多态性位点其等位基因频率与基因型频率差异均无统计学意义.RS10757278的A等位基因频率在男性胸主动脉夹层患者中的比例(59.4％)要高于男性高血压组(47.2％),差异有统计学意义(P=0.010).此外,利用Logisitic回归校正心血管疾病发病相关危险因素(包括年龄、血压、糖尿病、血脂异常及吸烟),发现该基因多态性是男性胸主动脉夹层发病的独立危险因素[比值比(OR)=0.61,95％可信区间(CI) =0.42 ～0.89)].结论 与细胞周期蛋白依赖酶抑制剂基因相关的单核苷酸多态性位点A等位基因是中国男性汉族人群胸主动脉夹层发病的重要遗传易感因素.     

服用卡马西平癫痫患者CYP3A4基因多态性的研究

目的:研究服用卡马西平癫痫患者细胞色素P4503A4(CYP3A4)的基因多态性,为临床制定卡马西平个体化给药方案提供依据。方法:收集临床服用卡马西平癫痫患者的血标本,用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法检测CYP3A4的突变。结果:141例患者中存在CYP3A4*4、CYP3A4*6的突变,个体突变率均为0.71%;未见CYP3A4*5的突变。结论:2例突变型标本与其他标本的血药浓度与临床疗效比较无显著性差异,不能说明CYP3A4*4、CYP3A4*6的突变对其表达的药物代谢酶的活性有影响。     

Polymorphisms and haplotypes of DNA repair and xenobiotic metabolism genes and risk of DNA damage in Chinese vinyl chloride monomer (VCM)-exposed workers

In this case-control study, we investigated the association between DNA damage and genetic susceptibility among vinyl chloride monomer (VCM)-exposed workers. The cumulative exposure dose of VCM was calculated based on the workers' duration of exposure and the geometric mean concentration of VCM in the workplace. DNA damage to peripheral blood lymphocytes was measured by single cell gel electrophoresis (SCGE) assay, and single nucleotide-polymorphisms (SNPs) in xenobiotic metabolism and DNA repair genes were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Univariate analysis showed that the CYP2E1 c1c2/c2c2 and XPD751 Lys/Gln and Gln/Gln genotypes were significantly associated with the levels of DNA damage (P<0.01 and 0.05, respectively). Further logistic regression analysis showed a significant association between CYP2E1 c1c2/c2c2 and DNA damage, and risk of having increased levels of DNA damage was more pronounced in those individuals having XRCC1 194 mutant genotypes and/or XPD751 Lys/Gln and Gln/Gln genotypes. Although most of the XPD and XRCC1 haplotypes did not show any significant difference, the XRCC1 haplotype Trp194-Arg280 was significantly over-represented in the case group (P<0.05; OR 2.09; 95% CI: 1.07-4.06) than in controls. Overall, our data suggest that the genotypes of CYP2E1, XRCC1 194, and XPD 751 were associated with the level of DNA damage and may contribute to individual sensitivity to DNA damage induced by VCM in the workplace.     

Assessment of Relationship between Fyn-related Kinase Gene Polymorphisms and Overweight/Obesity in Korean Population

The fyn-related kinase (FRK) belongs to the tyrosine kinase family of protein kinases. Recent studies have shown that Frk affects pancreatic beta cell number during embryogenesis and promotes beta cell cytotoxic signals in response to streptozotocin. To investigate the genetic association between FRK polymorphisms and the risk of obesity in Korean population, single nucleotide polymorphisms (SNPs) in the FRK gene region were selected and analyzed. The body mass index (BMI) was calculated, and biochemical data (systolic blood pressure, diastolic blood pressure, hemoglobin A1C, triglyceride, total cholesterol, high density lipoprotein, and low density lipoprotein) of blood sample from each subject were also measured. One hundred fifty five healthy control and 204 overweight/obesity subjects were recruited. Genotype frequencies of six SNPs [rs6568920 (+8391G>A), rs3756772 (+56780A>G), rs3798234 (+75687C>T), rs9384970 (+68506G>A), rs1933739 (+72978G>A), and rs9400883 (+75809A>G)] in the FRK gene were determined by Affymetrix Targeted Genotyping Chip data. According to the classification of Korean Society for the Study of Obesity, control (BMI 18 to <23) and overweight/obesity (BMI≥23) subjects were recruited. For the analysis of genetic data, EM algorithm, SNPStats, Haploview, HapAnalyzer, SNPAnalyzer, and Helixtree programs were used. Multiple logistic regression analysis (codominant, dominant, and recessive models) was performed. Age and gender as covariates were adjusted. For biochemical data, Student''s t test was used. The mean value of BMI in the control and overweigh/obesity groups was 21.1±1.2 (mean±SD) and 25.6±2.0, respectively. All biochemical data of the overweight/obesity group were statistically significance, compared with the control group. Among six SNPs, two linkage disequilibrium (LD) blocks were discovered. One block consisted of rs1933739 and rs9400883, and the other comprised rs3756772 and rs3798234. One SNP (rs9384970, +68506G>A) showed an association with overweight/obesity in the codominant model (p=0.03). Interestingly, the AA genotype distribution in the overweight/obesity group (n=7, 3.5%) was higher than those in the control group (n=1, 0.6%), which is not found in either Japanese or Chinese subjects. Therefore, the AA genotype of rs9384970 may be a risk factor for development of obesity in Korean population. The results suggest that FRK may be associated with overweight/obesity in Korean population.     

Race differences in factors relating to smoking initiation

To investigate race differences in retrospectively-reported early smoking experiences, we studied African-American (n = 48) and Caucasian (n = 155) current smokers who participated in a study designed to identify phenotypic and genotypic factors associated with smoking. Compared with Caucasian smokers, African-American smokers were less educated (mean ± s.e.m.: 13.3 ± 0.25 vs. 14.3 ± 0.16; p < .01), had higher BMI (28.9 ± 1.06 vs. 26.7 ± 0.52; p < .05), and smoked significantly fewer cigarettes/day (14.1 ± 1.00 vs. 18.4 ± 0.74; p < .01). Ninety percent of African-American smokers consumed menthol cigarettes, as opposed to 25% of Caucasian smokers. African-American smokers were significantly older than Caucasian smokers upon initial smoking experimentation (17.4 ± 1.1 vs. 14.7 ± 0.3; p < .05) and onset of regular smoking (19.7 ± 0.9 vs. 17.4 ± 0.4; p < .05). African-American smokers were significantly more likely than Caucasian smokers to endorse global pleasurable sensations (48% vs. 30%; p < .05), “pleasurable rush or buzz” (62% vs. 43%; p < .05), and “relaxing” (45% vs. 27%; p < .05) as early experiences with smoking, whereas Caucasian smokers were marginally more likely to report dizziness and difficulty inhaling (61% vs. 45%; p < .10 and 48% vs. 31%; p < .10, respectively). Caucasian smokers were significantly more likely to endorse friends (6.9 ± 0.2 vs. 4.8 ± 0.4; p < .0001) and “perk me up” (4.2 ± 0.3 vs. 3.1 ± 0.4; p < .05) and marginally more likely to endorse buzz (4.2 ± 0.2 vs. 3.4 ± 0.5; p < .10) as reasons for starting to smoke. Further research is needed to determine the relative contributions of genetic, developmental, and socio-cultural factors to these findings.     

Influence of phase-related variability in premenstrual symptomatology, mood, smoking withdrawal, and smoking behavior during ad libitum smoking, on smoking cessation outcome

Emerging evidence suggests that women have a more difficult time quitting smoking than men-possibly due, in part, to sex hormones. The present study characterized mood, premenstrual symptomatology, and smoking withdrawal, as well as smoking behavior, in the follicular and luteal phases during ad libitum smoking in 25 women intending to quit. We also investigated the possible influence of phase-related variability in these measures on likelihood of study adherence and smoking cessation. We found that premenstrual symptomatology, as well as some measures of mood and smoking withdrawal, were significantly higher during the luteal phase than in the follicular phase. Cigarettes/day did not vary by menstrual cycle phase. Phase-related variability in premenstrual symptomatology [F(3, 20)=2.82, p=0.0650)] and urge to smoke [F(2, 21)=4.85, p=0.0186)] were associated with relapse. These data support the inference that sex hormones influence smoking cessation outcome. This knowledge may contribute to the development of more rational and effective smoking cessation interventions for women.     

Failure to report attempts to quit smoking

Introduction

Accurately assessing quit attempt history is important to develop population estimates of cessation and to increase our understanding of smoking trajectories. Thus, the current study investigated failure to report quit attempts as a function of length of quit attempt by time since quit attempt over the past year.

Methods

The present study used data from the Smoking Toolkit Study, a series of population-based surveys of smokers and recent ex-smokers in England aged 16 years and older. Among the 11,772 smokers identified at baseline (24.4% of the total sample), this study focused on the 4234 participants (36.0% of current smokers) who reported between one and three quit attempts in the past year.

Results

There was a strong trend for quit attempts that lasted for shorter periods of time to fail to be reported. After three months, 90.1% of those lasting less than one day, 63.7% of those lasting between a day a one week, and 38.9% of those lasting between one week and one month failed to be reported.

Conclusion

A large proportion of unsuccessful quit attempts fail to be reported, particularly if they only last a short time or occurred longer ago. Therefore, population estimates of quit attempts based on retrospective data may be considerable underestimates and estimates of the success of quit attempts may be overestimates. Future research is needed to establish whether there is differential reporting of quit attempts as a function of features of attempts such as use of cessation aids.     

A further investigation of the relations of anxiety sensitivity to smoking motives

Prior research has shown that anxiety sensitivity (AS) is associated with smoking to reduce negative affect (e.g., [Comeau, N., Stewart, S.H., & Loba, P., (2001). The relations of trait anxiety, anxiety sensitivity and sensation seeking to adolescents' motivations for alcohol, cigarette, and marijuana use. Addictive Behaviors, 26, 803-825.]). However, given limitations in the measurement of smoking motives in previous AS studies, it has yet to be definitively established that AS is specifically related to negative reinforcement smoking motives. Moreover, the overall AS construct is comprised of three lower-order components: physical, psychological, and social concerns (e.g., [Stewart, S.H., Taylor, S., & Baker, J.M., (1997). Gender differences in dimensions of anxiety sensitivity. Journal of Anxiety Disorders, 11, 179-200.]). Previous investigations generally have not examined the relative contributions of each of these three AS components to smoking for negative reinforcement motives. The present study attempted to address each of these gaps in the literature. A sample of 119 smokers attending a tobacco intervention program (see [Mullane, J.C., Stewart, S.H., Rhyno, E., Steeves, D., Watt, M., & Eisner, A., (2008). Anxiety sensitivity and difficulties with smoking cessation. In A.M. Columbus (Ed.), Advances in Psychological Research (vol. 54A, pp. 141-155). Hauppauge, NY: Nova Science Publishers.]) completed the Anxiety Sensitivity Index (ASI; [Peterson, R.A., & Reiss, S., (1992). The Anxiety Sensitivity Index manual (2nd ed.). Worthington, OH: International Diagnostic Services.]) and the Reasons For Smoking scale (RFS; [Ikard, F.F., Green, D.E., & Horn, D., (1969). A scale to differentiate between types of smoking as related to the management of affect. International Journal of the Addictions, 4, 649-659.]) at pre-treatment. In a principal components analysis (PCA) of the RFS items, stringent parallel analysis supported a two-factor solution (negative and positive reinforcement smoking motives) as opposed to the intended six factors ([Ikard, F.F., Green, D.E., & Horn, D., (1969). A scale to differentiate between types of smoking as related to the management of affect. International Journal of the Addictions, 4, 649-659.]). ASI total scores were significantly positively correlated with both RFS factors in bivariate correlational analyses. In partial correlations, the relation between the ASI and the RFS negative reinforcement factor remained significant when controlling for RFS positive reinforcement smoking motives, but the correlation of ASI with RFS positive reinforcement motives was not significant after controlling for RFS negative reinforcement motives. At the level of AS components, AS psychological concerns were related to both negative and positive reinforcement motives, while AS physical concerns were more strongly related to negative reinforcement motives. Implications for designing targeted tobacco interventions for high AS smokers are discussed.     

Impulsivity-like traits and smoking behavior in college students

Recent research has deconstructed the concept of impulsivity by identifying five different traits that influence engagement in impulsive behaviors: positive urgency (tendency to act rashly in response to a positive mood), negative urgency (tendency to act rashly in response to a negative mood), sensation seeking, lack of planning, and lack of perseverance. The traits are only moderately related to each other. The aim of this study was to apply this advance to the study of smoking. We tested a two-stage hypothesis: Higher sensation seeking was hypothesized to differentiate current smokers from non-smokers, and negative and positive urgencies were expected to predict concurrent level of nicotine dependence among smokers. As anticipated, greater sensation seeking was associated with a higher odds of being a current smoker (odds ratio = 1.51). Greater positive urgency, but not other impulsivity-related traits, was associated with significantly higher levels of nicotine dependence, explaining 29% of the variance in level of nicotine dependence.     

Transdermal nicotine in smoking cessation

Summary A systematic search of the literature was made to identify relevant reports of clinical trials of transdermal nicotine, followed by detailed statistical analysis of the results to calculate a pooled estimate of the rate of smoking cessation. Both a fixed effect and a random effects model were used to calculate pooled estimates.The pooled odds ratio (OR) for short-term smoking cessation in favour of the transdermal patches was OR=3.10. Using a random effects model, the risk difference (RD) in favour of the transdermal patches was RD=0.25. The corresponding values for long-term cessation were OR=2.26 and RD=0.11. Skin irritation was a common adverse effect with incidence rates ranging up to about 70%.Nicotine transdermal patches were effective in promoting smoking cessation both in the short-term, with assessments at 3 to 10 weeks, and in the long-term, with assessment at 24 to 52 weeks. Long-term abstinence rates in subjects treated with nicotine patches for a few weeks remained higher than in subjects treated with placebo patches. Adverse effects were usually minor and transient, although subjects with a sensitive skin may find the applications intolerable. Further studies are required to confirm the value of nicotine patches in promoting smoking cessation in the absence of professional medical support and in general medical practices in the community.