APOE ɛ4, an Alzheimer's disease susceptibility allele, and smoking cessation.

Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.

Genetic variation in nicotine metabolism predicts the efficacy of extended-duration transdermal nicotine therapy.

In a placebo-controlled trial, we examined the efficacy of a 6-month ("extended") transdermal nicotine therapy vs. the 8-week ("standard") therapy in 471 Caucasian smokers with either normal or reduced rates of nicotine metabolism as determined at pretreatment. Extended therapy was superior to standard therapy in genotypic or phenotypic reduced metabolizers (RMs) of nicotine but not in normal metabolizers (NMs). RMs of nicotine are candidates for extended transdermal nicotine therapy, whereas an alternative therapeutic approach may be needed for those with normal rates of nicotine metabolism.

Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype.

The val allele of the catechol-O-methyltransferase (COMT) val(158)met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n=33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)>or=14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P=0.0005), left DLPFC (P=0.02) and dorsal cingulate/medial prefrontal cortex (P=0.01) as well as for task reaction time (P=0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain-behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

Maternal smoking during late pregnancy and offspring smoking behaviour.

We explored the influence of maternal smoking during late pregnancy on the likelihood of smoking among offspring in adolescence and adulthood, using birth cohort data collected in the United Kingdom as part of the 1958 National Child Development Study. Longitudinal analysis indicated that maternal smoking during late pregnancy was associated with an increased likelihood of being a non-smoker at 16-year, 23-year and 33-year follow-up. This association differed between male and female offspring, with women showing no significant association and men showing an increased likelihood of being a non-smoker. There did not appear to be any association between maternal smoking during late pregnancy and cigarette consumption among offspring who reported smoking for either sex. These results are inconsistent with some previous reports that maternal smoking during pregnancy increases the likelihood of smoking among female offspring, although the observation of a moderating effect of sex on smoking behaviour is consistent with several previous reports. We discuss possible mechanisms for this association, and suggest factors that may account for the observed sex differences in this association, and the discrepancy between our results and some previous reports.

Interaction between variation in the D2 dopamine receptor (DRD2) and the neuronal calcium sensor-1 (FREQ) genes in predicting response to nicotine replacement therapy for tobacco dependence.

We have previously demonstrated that a functional dopamine D2 receptor promoter variant (DRD2 -141 Ins/Del) predicts response to nicotine replacement therapy (NRT). The present study extends this finding in the same population of 363 NRT-treated subjects, by examining variation in the gene encoding the neuronal calcium sensor-1 protein (FREQ), which functions to regulate D2 receptor desensitization. The results indicate a statistically significant interaction effect of DRD2-141 and FREQ genotypes on abstinence at the end of the NRT treatment phase; 62% of the smokers with at least one copy of the DRD2 -141 Del allele and two copies of the FREQ rs1054879 A allele were abstinent from smoking, compared to 29-38% abstinence rates for other smokers in the trial. This result suggests that the interaction between variation in the DRD2 and FREQ genes, which both encode components of the D2 dopamine receptor signal transduction pathway, impacts the efficacy of NRT.

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Human esophageal cancer is distinguished from adjacent esophageal tissue by tissue cysteine concentrations.

Recent studies have suggested that cysteine, in addition to glutathione, may play a role in the genesis, pathobiology, and treatment response of rodent and human cancers. We examined the relative concentrations of cysteine and glutathione in human esophageal cancer and adjacent, minimally involved esophageal tissue. Small biopsies from tumors and adjacent esophageal tissues were placed into cold acid to allow extraction of low-molecular-mass compounds and simultaneous precipitation of macromolecules. Supernatants were analyzed by high-performance liquid chromatography with electrochemical detection for thiol content. While there was no statistically significant difference between the glutathione content of tumor versus adjacent tissue (2.2 mM vs 2.1 mM, respectively), tumor tissue had significantly higher levels of cysteine than adjacent tissue (0.21 mM vs 0.13 mM, respectively). In conclusion, cysteine content distinguishes tumor from adjacent more normal tissue.

Risk factors for lyme disease in Chester County, Pennsylvania.

OBJECTIVE: To identify factors associated with increased or decreased risk of infection for Lyme disease in Chester County, Pennyslvania. METHODS: The authors designed an unmatched case-control study involving 294 incident cases reported to the Chester County Health Department in 1998 and 449 controls selected by random digit dialing. All case and control participants were interviewed by telephone. RESULTS: Age is a risk factor for Lyme disease for groups aged 10-19 years old and 50 years or older. Sex was not a risk factor. Incidence of Lyme disease in a rural setting was three times the incidence in an urban setting. Increased risk also was associated with living in single family homes, homes with yards or attached land, woods on the land, signs of tick hosts seen on the land, and homes within 100 feet of woodland. Gardening for more than four hours per week was also a risk factor, but most other outdoor activities were not. Twice as many participants took protective measures against tick bites before outdoor employment than those who merely ventured into the yard or land associated with the home. Only checking for ticks during outdoor activity and the use of repellents prior to outdoor activities outside the yard were unequivocally associated with a reduced risk of Lyme disease. CONCLUSIONS: It is important to increase public awareness about the risk of acquiring Lyme disease from ticks in the immediate environment of the home.