Environmental Smoking and Smoking Onset in Adolescence: The Role of Dopamine-Related Genes. Findings from Two Longitudinal Studies

Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents'' and friends'' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends'' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system.     

酒精依赖综合征患者DRD2、DRD4和DAT基因多态性的研究

目的:探讨云南地区人群中DRD2(TaqIA、-141C)、DRD4和DAT基因多态性与酒精依赖的相关性.方法:采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)分析技术以及聚合酶链式反应-可变数目串联重复序列多态性(PCR-VNTR)分析技术检测酒依赖组(80例)和对照组(70例)在3个候选基因中的基因型和等位基因频率.结果:上述三个基因多态性的基因型和等位基因频率在酒依赖组和对照组中差异均无统计学意义(P>0.05),对DRD2基因中的TaqIA和-141C进行单倍型分析时发现,Del/Al是一种保护单倍型,能抑制酒依赖综合征的发生.结论:在云南地区人群中,携带有Del/Al单倍型基因的人不易形成酒依赖.     

Dopamine Genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and Executive Function: Their Interaction with Obesity

Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.     

Dopamine transporter (DAT1) and dopamine receptor D4 (DRD4) genotypes differentially impact on electrophysiological correlates of error processing

Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing--the error-related negativity (ERN) and the error positivity (Pe)--are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes.     

Risk Heterogeneity and Recurrent Violent Victimization: The Role of DRD4

For some people, victimization comes with significant costs. One of these costs is the likelihood of being victimized a subsequent time. Unfortunately, research shows that a portion of victims do in fact experience more than one victimization. Although this likelihood has been established, the reasons why some people are victimized more than once are not fully understood. One explanation centers on individual risk factors that, if left unchanged, will increase risk of further victimization. Previously unstudied, however, are genetic factors that may place and keep a victim at risk, even after an initial victimization. Using data from the National Longitudinal Study of Adolescent Health, the current study addresses this gap. The findings reveal that there is in fact a genetic factor, the 7R allele of the DRD4 gene, that distinguishes individuals who have been victimized once from those who have been victimized multiple times.     

Evolution of exon 1 of the dopamine D4 receptor (DRD4) gene in primates

The dopamine D4 receptor (DRD4) gene exhibits a large amount of expressed polymorphism in humans. To understand the evolutionary history of the first exon of DRD4-which in humans contains a polymorphic 12bp tandem duplication, a polymorphic 13bp deletion, and other rare variants-we examined the homologous exon in thirteen other primate species. The great apes possess a variable number of tandem repeats in the same region as humans, both within and among species. In this sense, the 12bp tandem repeat of exon 1 is similar to the 48bp VNTR of exon 3 of DRD4, previously shown to be polymorphic in all primate species examined. The Old World monkeys show no variation in length, and a much higher conservation of amino acid sequence than great apes and humans. The New World monkeys show interspecific differences in length in the region of the 12bp polymorphism, but otherwise show the higher conservation seen in Old World monkeys. The different patterns of variation in monkeys compared to apes suggest strong purifying selective pressure on the exon in these monkeys, and somewhat different selection, possibly relaxed selection, in the apes.     

Phosphatidylinositol 3-kinase,protein kinase C,and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites

The dopamine transporter (DAT) modulates dopamine neurotransmission and is a primary target for psychostimulant influences on locomotion and reward. Selective DAT expression by dopaminergic neurons has led to use of cocaine analog DAT radioligands to assess rates of progression of dopamine neuronal degeneration in Parkinson's disease. We have documented that DAT is a phosphoprotein that is regulated by phosphorylation through pathways that include protein kinase C cascades. We now extend this work using drugs selective for phosphatidylinositol 3-kinase (PI3K), protein kinase C, MEK1/2, p38 kinase, and Ca2+/calmodulin kinase II. We compare the drug effects on wild type DAT to the effects on 20 DAT mutants and a DAT deletion. PI3K and MEK1/2 modulators exert strong effects on DAT expression patterns and dopamine uptake Vmax. PKC principally modulates Vmax. Neither p38 nor Ca2+/calmodulin kinase II agents exert significant influences on wild type DAT. Several mutants and a DAT with an N-terminal deletion display alterations that interact with the effects of kinase modulators, especially S7A for PKC effects; T62A, S581A, and T612A for PI3K effects; and S12A and T595A mutants for MEK1/2 effects. 32P-Labeling studies confirm several of these effects of kinase pathway modulators on DAT phosphorylation. DAT expression and activities can be regulated by kinase cascades that require phosphoacceptor sites most concentrated in its N terminus. These results have a number of implications for DAT regulation and mandate caution in using DAT radioligand binding to infer changes in dopaminergic neuronal integrity after treatments that alter activities of these kinase pathways.     

Role of dopamine transporter (DAT) in dopamine transport across the nasal mucosa

Dopamine is a catecholamine neurotransmitter necessary for motor functions. Its deficiency has been observed in several neurological disorders, but replacement of endogenous dopamine via oral or parenteral delivery is limited by poor absorption, rapid metabolism and the inability of dopamine to cross the blood-brain barrier. The intranasal administration of dopamine, however, has resulted in improved central nervous system (CNS) bioavailability compared to that obtained following intravenous delivery. Portions of the nasal mucosa are innervated by olfactory neurons expressing dopamine transporter (DAT) which is responsible for the uptake of dopamine within the central nervous system. The objective of these studies was to study the role of DAT in dopamine transport across the bovine olfactory and nasal respiratory mucosa. Western blotting studies demonstrated the expression of DAT and immunohistochemistry revealed its epithelial and submucosal localization within the nasal mucosa. Bidirectional transport studies over a 0.1-1 mM dopamine concentration range were carried out in the mucosal-submucosal and submucosal-mucosal directions to quantify DAT activity, and additional transport studies investigating the ability of GBR 12909, a DAT inhibitor, to decrease dopamine transport were conducted. Dopamine transport in the mucosal-submucosal direction was saturable and was decreased in the presence of GBR 12909. These studies demonstrate the activity of DAT in the nasal mucosa and provide evidence that DAT-mediated dopamine uptake plays a role in the absorption and distribution of dopamine following intranasal administration.     

Theoretical studies on densities, stability and detonation properties of 2D polymeric complexes Cu(DAT)2Cl2 and its new analogues Zn(DAT)2Cl2

A novel environmentally friendly octahedrally coordinated 2D polymeric complexes bis(1,5-diaminotetrazole) -dichlorozinc(II) (Zn(DAT)₂Cl₂) was first designed based on the the crystal data of bis(1,5-diaminotetrazole)- dichlorocopper(II) (Cu(DAT)₂Cl₂). Density functional theory (DFT) was used to predict the optimized geometries at TPSSTPSS/6-311G(d, p) level. Densities and detonation properties were evaluated using the electron cloud enclosed volume and VLW equation of state (VLW EOS), respectively. Calculation results show that the density of Zn(DAT)₂Cl₂ (2.117 g?·?cm^?1) is a bit more than that of Cu(DAT)₂Cl₂ (2.106 g?·?cm^?1). The calculated high positive heat of formation (HOF) predicts that the stabilities of the title compounds decrease in the order Zn(DAT)₂Cl₂ > Cu(DAT)₂Cl₂, which agrees with the result of bond dissociation energies (BDE). Even though they have the same molecule structures, their first scission steps are different. Furthermore, the title two compounds show good detonation velocities and pressures compared with that of bis-(5-nitro-2H-tetrazolato-N ²) tetraamminecobalt(III) perchlorates (BNCP), and they are potential candidates for high-energy-density materials (HEDM).     

The Systemic Immune Network in Recent Onset Type 1 Diabetes: Central Role of Interleukin-1 Receptor Antagonist (DIATOR Trial)

Background

The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.

Methods and Findings

All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18–39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25–0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.

Conclusions

In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.

Trial registration

ClinicalTrials.gov registration number: {"type":"clinical-trial","attrs":{"text":"NCT00974740","term_id":"NCT00974740"}}NCT00974740     

1，2，4－三氯苯在土壤中的降解

在好氧和厌氧两种条件下研究了１,２,４－三氯苯的降解,结果表明,１,２,４－三氯苯的好氧降解和厌氧降解均遵循一级反应动力学在同样水分、温度及初始浓度条件下,１,２,４－三氯苯的好氧降解比厌氧降解迅速,其半衰期分别为１．８９～５．８６和５．０７～１９．０８ｄ土壤中１,２,４－三氯苯的初始浓度对于其降解也有显著影响,在０～１００μｇ·ｇ－１的范围内,浓度增高时,其降解加快,说明污染物浓度对降解的影响;在１０～３０℃范围内,温度增高导致降解过程加快,归因于温度升高对微生物酶活性的激活作用．     

CYP1A1、CYP1B1、NET、DAT1单个和联合基因型与汉族人群乳腺癌易感性的研究（英文）

乳腺癌是最常见的女性癌症,其发生是遗传因素和环境因素相互作用的结果。因此,我们就CYP1A1MspⅠ(m1多态)、CYP1B1 Leu432Val、NET T-182C、DAT1-VNTR等基因多态性对新疆汉族人群乳腺癌易感性的研究进行探讨。在以144例乳腺癌患者和120例正常对照组为研究对象的病例-对照研究中,发现CYP1A1MspⅠ位点CC基因型、C等位基因(OR=3.32,95%CI:1.24~8.86;OR=1.58,95%CI:1.09~2.31)和高风险联合基因型CYP1A1 MspⅠ与CYP1B1 Leu432Val,CYP1A1 MspⅠ与DAT1-VNTR,CYP1B1 Leu432Val与DAT1-VNTR(OR=2.43,95%CI:1.23~4.78;OR=4.53,95%CI:1.26~16.27;OR=2.98,95%CI:1.10~8.06)与乳腺癌风险增加有关。CYP1B1、NET和DAT1基因多态性与乳腺癌易感性无关。这些研究结果表明,CYP1A1 MspⅠ多态性和CYP1A1、CYP1B1、DAT1高风险联合基因型能增加新疆汉族人群患乳腺癌的风险。     

D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects.

Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting protein structure in the D4 dopamine-receptor gene (DRD4) in a sample of 341 American subjects, of whom 224 are of primarily European ancestry and 117 are of primarily African ancestry. These subjects had diagnoses of substance dependence or personality disorder (PD) or were screened to exclude major psychiatric diagnosis. We found that, although the substance-dependent subjects had significantly higher novelty seeking than the control and PD subjects, they did not differ in DRD4*7R allele frequency. There was no association between any DRD4 polymorphism and novelty seeking in any population or diagnostic group, except for a significant association between the DRD4*7R allele and lower novelty seeking among European American females and African American substance abusers. The novelty seeking of subjects heterozygous for a null mutation did not differ from that of subjects with two functional alleles. We conclude that the most likely explanation of these results is that the DRD4 VNTR does not influence directly the trait of novelty seeking, in these samples.     

Dopamine D1, D2, D3 Receptors,Vesicular Monoamine Transporter Type-2 (VMAT2) and Dopamine Transporter (DAT) Densities in Aged Human Brain

The dopamine D₁, D₂, D₃ receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77–107.8, mean: 91 years) by quantitative autoradiography. The density of D₁ receptors, VMAT2, and DAT was measured using [³H]{"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, [³H]dihydrotetrabenazine, and [³H]WIN35428, respectively. The density of D₂ and D₃ receptors was calculated using the D₃-preferring radioligand, [³H]WC-10 and the D₂-preferring radioligand [³H]raclopride using a mathematical model developed previously by our group. Dopamine D₁, D₂, and D₃ receptors are extensively distributed throughout striatum; the highest density of D₃ receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10–20-fold lower than that of VMAT2 in striatal regions. Dopamine D₃ receptor density exceeded D₂ receptor densities in extrastriatal regions, and thalamus contained a high level of D₃ receptors with negligible D₂ receptors. The density of dopamine D₁ linearly correlated with D₃ receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D₃ receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D₁ and D₂ receptors and DAT compared with the aged rhesus monkey brain. The differential density of D₃ and D₂ receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D₂ or D₃ receptors.     

Intraspecific Variability in Parenting Styles of Rhesus Macaques (Macaca mulatta): The Role of the Social Environment

This study tested the hypothesis that differences in parenting styles between two captive populations of rhesus macaques, one living in the UK (Madingley) and the other in the USA (Yerkes), are associated with differences in the degree to which social interactions with other group members pose a risk to infants. Twenty-eight mother–infant dyads, 17 living at Madingley and 11 at Yerkes, were observed for 24 h during the first 12 wks of infant life. Mother–infant dyads living at Madingley spent a higher percentage of time in contact than those living at Yerkes. The Madingley mothers also restrained and retrieved their infants more often, and rejected them less often than the Yerkes mothers. Consistent with the prediction, the protective parenting style of the Madingley mothers was associated with higher frequency of infant kidnapping and higher risk of infant harassment from other group members. Interpopulation differences in risks to infants and parenting styles are likely to be the result of differences in social density in the two environments rather than differences in the matrilineal structure of the two populations.     

The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus

Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (approximately 40000-50000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between receptor variants.     

The Association of Four Common Polymorphisms from Four Candidate Genes (COX-1, COX-2, ITGA2B,ITGA2) with Aspirin Insensitivity: A Meta-Analysis

Objective

Evidence is mounting suggesting that a strong genetic component underlies aspirin insensitivity. To generate more information, we aimed to evaluate the association of four common polymorphisms (rs3842787, rs20417, rs201184269, rs1126643) from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity via a meta-analysis.

Methods and Results

In total, there were 4 (353/595), 6 (344/698), 10 (588/878) and 7 (209/676) articles (patients/controls) qualified for rs3842787, rs20417, rs20118426 and rs1126643, respectively. The data were extracted in duplicate and analyzed by STATA software (Version 11.2). The risk estimate was expressed as odds ratio (OR) and 95% confidence interval (95% CI). Analyses of the full data set indicated significant associations of rs20417 (OR; 95% CI; P: 1.86; 1.44–2.41; <0.0005) and rs1126643 (2.37; 1.44–3.89; 0.001) with aspirin insensitivity under allelic model. In subgroup analyses, the risk estimate for rs1126643 was greatly potentiated among patients with aspirin semi-resistance relative to those with aspirin resistance, especially under dominant model (aspirin semi-resistance: 5.44; 1.42–20.83; 0.013 versus aspirin resistance: 1.96; 1.07–3.6; 0.03). Further grouping articles by ethnicity observed a stronger prediction of all, but rs20417, examined polymorphisms for aspirin insensitivity in Chinese than in Caucasians. Finally, meta-regression analyses observed that the differences in percentage of coronary artery disease (P = 0.034) and averaged platelet numbers (P = 0.012) between two groups explained a large part of heterogeneity for rs20417 and rs1126643, respectively.

Conclusion

Our findings provide strong evidence that COX-2 and ITGA2 genetic defects might increase the risk of having aspirin insensitivity, especially for aspirin semi-resistance and in Chinese populations.