A mutation in the Duffy antigen (DARC) that abrogates receptor expression and gives profound protection against some malaria species has become almost universal in African populations. He et al. ...(2008) show that this polymorphism also leads to significantly increased susceptibility to HIV-1 infection but, paradoxically, to prolonged survival in HIV-1-infected subjects.
Cytochrome P450 2B6 (CYP2B6) has a role in the metabolism of many clinically important substances, but the variation within the CYP2B6 gene has not been fully characterized. The aim of the present ...study was to develop a reliable and robust assay for determining genotypic variants.
We used a two-stage procedure. An initial multiplex PCR reaction amplified the relevant gene fragments in exonic and regulatory regions to ensure isolation of CYP2B6 from its similar pseudogene (CYP2B7). This product was then genotyped by allele-specific PCR.
The assay detected the following published single-nucleotide polymorphisms: C64T (Arg22Cys), C78T, G216C, G516T (Gln172His), C777A (Ser259Arg), A785G (Lys262Arg), and C1459T (Arg487Cys), as well as additional loci found within the single-nucleotide polymorphism (SNP) databases: A1190G, C1268A, C1330T, A1382G, A1402T, and an A/T SNP in intron 2 (A12917T). This approach detected all common, previously reported alleles and identified a new allele (CYP2B6*4C) present in 2.2% of a Caucasian population. Genotypic frequencies obtained were consistent with previously published results.
This method is simple, reliable, rapid, and amenable to automation and could facilitate the large-scale genotypic analysis of CYP2B6.
To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on ...cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs-suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.
Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.
Polymorphisms in CYP2C19 and CYP2C9 ...in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.
All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071).
CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.
Bupropion hydrochloride is effective in promoting long-term abstinence from smoking and may reduce risk for relapse through attenuation of withdrawal symptoms and craving. Bupropion is a weak ...dopamine reuptake inhibitor, and individual genetic variation in the dopamine D2 receptor has been associated with nicotine dependence in case–control studies. Thirty smokers were randomly assigned to bupropion or placebo and interviewed using the Minnesota Nicotine Withdrawal Scale on two occasions: prior to starting medication and after 14 days on bupropion or placebo. The individual symptoms of craving, irritability, and anxiety were significantly reduced in the bupropion group, whereas no withdrawal symptoms were diminished in the placebo group. Within the bupropion group, subgroup analyses with stratification by genotype demonstrated that craving, irritability, and anxiety were significantly attenuated only among subjects with DRD2-Taq1 A2/A2 genotypes. In the DRD2-Taq1 A1/A1 and A1/A2 groups, no significant reduction was seen in any individual symptom of the nicotine withdrawal syndrome. These data suggest that bupropion attenuates specific symptoms of the nicotine withdrawal syndrome and that this effect may be modified by genotype for the dopamine D2 receptor.
Considerable evidence indicates that smoking behavior is under a degree of genetic influence. We conducted a systematic review of candidate gene studies of smoking behavior and, where sufficient ...studies existed, combined reported data using meta-analytic techniques. A total of 41 studies were identified by the search strategy, of which 28 contributed to the meta-analysis. The meta-analysis included data on the DRD2, DAT, 5HTT, and CYP2A6 genes and smoking behavior. Categorical data were extracted on smoking status (never-smoker, ex-smoker, current smoker). Continuous data were extracted on number of cigarettes smoked per day. Evidence indicated effects of the DRD2 Taq1A polymorphism and smoking initiation, the 5HTT LPR and CYP2A6 reduced-activity polymorphisms and smoking cessation, and the DRD2 Taq1A and CYP2A6 reduced-activity polymorphisms and cigarette consumption. The evidence for an effect of specific genes was modest, however, and evidence indicated substantial between-study heterogeneity in most cases, with the exception of the effects of the 5HTT and CYP2A6 genes on smoking cessation. When a random-effects model was applied to analyses in which evidence indicated significant heterogeneity, the effects were in all cases no longer statistically significant. The evidence for a contribution of specific genes to smoking behavior remains modest. Implications for the design of future studies are discussed, such as the need for the development of more specific phenotypes to increase the genetic signal in candidate gene studies.
We investigated the association of catechol O- methyltransferase ( COMT ) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using
...either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation
attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype × treatment interaction
effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on
likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate
that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit
of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results
suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies,
but indicate that different genes influencing various components of this pathway may have different effects on response to
smoking cessation pharmacotherapy. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1065–9)
We sought to replicate previous studies reporting a moderating effect of the 5HTT gene on the association between trait neuroticism and smoking behaviour, and extend on this work by including a ...formal test of this interaction, in a sample of 141 heavy smokers. Nicotine dependence was measured using the Fagerström Test for Nicotine Dependence; trait neuroticism was assessed using the Eysenck Personality Questionnaire. All participants were genotyped for the 5HTT-LPR polymorphism.
A 3
×
2 ANOVA of nicotine dependence score, with genotype (L/L, L/S, S/S) and neuroticism (high, low) as between-subjects factors, indicated a significant main effect of genotype (
F2, 135
=
3.13,
p
<
0.05) in the predicted direction, with the short allele of the 5HTT gene being associated with higher nicotine dependence score. There was a marginal effect of neuroticism (
F1, 135
=
3.01,
p
=
0.08) in the predicted direction, with high trait neuroticism being associated with higher nicotine dependence score. The interaction effect was non-significant (
F
<
1).
These data suggest that 5HTT genotype is associated with nicotine dependence independently of any association between this gene and trait neuroticism that may modulate smoking behaviour. We failed to replicate the finding of a moderating influence of 5HTT genotype on the association between neuroticism and nicotine dependence.
Abstract
Beginning with the 1972 presidential election and for each election thereafter Harvard University's Institute of Politics in the John F. Kennedy School of Government has held a post-election ...symposium where all of the campaign managers, pollsters, political consultants and media advisors for all of the primary and general election candidates come together with leading journalists, electronic and print, and political commentators and pundits to discuss and dialogue about what occurred during the election among the candidates, nominees, and the winner and losers. The symposia have allowed campaign managers to describe what happened and forecast for the forthcoming presidential election. After the multi-day symposium a book length transcript is published. In 1992 the Annenberg School of Communication at the University of Pennsylvania launched its own symposia where the campaign managers of the Democratic and Republican nominees in the general election are invited to discuss what happened and forecast for the next presidential election. The ten books in the Harvard series and the three books in the Pennsylvania series are used as data sources in this article to determine if any of the campaign managers forecasted and/or predicted an African American presidential candidate, even when such candidates had appeared in previous years. While our findings uncover some of the interests and concerns of presidential campaign managers and advisors since 1972, the overriding focus of the symposia has been on the nature, scope, and significance of the African American electorate.
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