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Biomedical subjects

Gary E Swan

Publications and source records attributed to Gary E Swan.

At least 19 recordsLinked to original sources
PubMed2006

Novel genes identified in a high-density genome wide association study for nicotine dependence.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Case-Control Studies↗
PubMed2006

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Adult↗
PubMed2006

Longitudinal genetic analysis of executive function in elderly men.

The objective of this study was to characterize the relative contribution of genetic and environmental influences to individual differences in longitudinal performance and decline of executive function (EF) using a population-based prospective study of male, WWII veteran twins (NHLBI twin study). Three tests of EF were administered when the twins were 59-70 years old, with 9- and 13-year follow-up. APOE epsilon4 allele status was incorporated in the genetic models to determine its contribution to longitudinal genetic variability. Mean EF performance significantly worsened over time. EF performance was highly genetically correlated across repeat assessment. There were significant genetic influences on 9- and 13-year decline in digit symbol performance. For all tasks decline over the last 4-year follow-up was influenced by individual-specific environmental effects. Controlling for APOE epsilon4 allele presence did not appreciably change the magnitude of genetic effects. These results suggest that common genetic factors underlie longitudinal EF task performance. Genetic influences on EF decline, however, appear to be evident at longer time intervals between assessments.

Aged↗
PubMed2006

Heritability of cigarette smoking and alcohol use in Chinese male twins: the Qingdao twin registry.

BACKGROUND: China has the world's largest concentration of smokers (350 million) and rising alcohol consumption, yet little is known about tobacco and alcohol use aetiology. In 2000, the Chinese National Twin Registry was established to provide a genetically informative resource for investigation of health behaviour including tobacco and alcohol use. METHODS: Using standard twin methodology, this study aimed to examine the relative contribution of genetic and environmental influences on cigarette smoking and alcohol drinking in a sample of adult Chinese twins (n = 1010 individual twins). More than half of the male twins were smokers (58%), and 32.5% reported alcohol consumption. Among male smokers, 46.4% smoked 20 or more cigarettes per day (heavy smokers) and among drinkers, 32.8% consumed one or more drinks per day. Nearly all female twins were non-smokers (99.2%) and non-drinkers (98.7%); therefore, genetic analysis was limited to male data. RESULTS: In men, current smoking was significantly heritable [75.1%, 95% confidence interval (CI) 56.7-87.5] with no evidence for a significant contribution of shared environmental effects. Heavy smoking was more strongly influenced by genes (66.2%, 95% CI 0-88.4) than shared environment (8.7%, 95% CI 0-71.0). Similarly, current drinking was more strongly influenced by genetic effects (59.5%, 95% CI 0-87.8) than by shared environmental effects (15.3%, 95% CI 0-72.1). Amount of alcohol consumed was influenced to a similar degree by genetic (42.4%, 95% CI 0-91.8) and shared environmental factors (39.2%, 95% CI 0-82.7). CONCLUSIONS: These results support findings from twins of Western origin on the aetiology of tobacco and alcohol use and encourage further work in Chinese twins.

Adult↗
PubMed2006

Mutagen sensitivity has high heritability: evidence from a twin study.

Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

Genetic Predisposition to Disease↗
PubMed2006

A genome-wide screen for nicotine dependence susceptibility loci.

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Family Health↗
PubMed2006

Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.

OBJECTIVE: The impact of CYP2A6*21 (K476R) on in vivo nicotine metabolism and disposition was investigated. METHODS: A two-step allele-specific PCR assay was developed to detect the 6573A>G single nucleotide polymorphism (SNP) in CYP2A6*21. Nicotine metabolism phenotypes from a previously described intravenous labeled nicotine and cotinine infusion study [1] was used to assess the impact of CYP2A6*21. Genomic DNA samples from 222 (111 monozygotic and dizygotic twin pairs) Caucasian subjects were genotyped for CYP2A6 alleles (CYP2A6*1X2, -*1B, -*2, -*4, -*7, -*9, -*10, -*12, and -*21). The pharmacokinetic parameters were compared between individuals with no detected CYP2A6 variants (CYP2A6*1/*1, n = 163) and individuals heterozygous for the CYP2A6*21 allele (CYP2A6*1/*21, n = 9). RESULTS: The frequency of the CYP2A6*21 allele was found to be 2.3% in Caucasians (n = 5/222 alleles, evaluated in one twin from each twin pair). In vivo pharmacokinetic parameters, such as nicotine clearance (1.32+/-0.37 vs. 1.18+/-0.20 L/min), fractional clearance of nicotine to cotinine (1.02+/-0.36 vs. 0.99+/-0.23 L/min), nicotine half-life (111+/-37 vs. 116+/-29 min), and the trans-3'-hydroxycotinine to cotinine ratio (1.92+/-1.0 vs. 1.55+/-0.58) indicated no substantial differences in nicotine metabolism between those without the variant (CYP2A6*1/*1, n = 163) and those with the variant (CYP2A6*1/*21, n = 9), respectively. CONCLUSIONS: CYP2A6*21 does not have a detectable impact on nicotine metabolism in vivo. Our data suggest that CYP2A6*21 may not be important for future studies of nicotine metabolism and the resulting impacts on smoking behaviors.

Alleles↗
PubMed2006

Female sex and oral contraceptive use accelerate nicotine metabolism.

BACKGROUND: Several studies have reported that female smokers have a higher risk of lung cancer than male smokers. This could be related to sex differences in nicotine metabolism and related smoking behavior. This study tested the hypothesis that women metabolize nicotine more rapidly than men and that, among women, oral contraceptive users metabolize nicotine more rapidly than nonusers of oral contraceptives. METHODS: Two hundred seventy-eight healthy volunteers who were twins and 16 who were siblings of twins, recruited from the Northern California Twin Registry, received an infusion of deuterium-labeled nicotine and cotinine with frequent blood sampling. The plasma clearances of nicotine and cotinine, the clearance of nicotine to cotinine (an index of cytochrome P450 [CYP] 2A6 activity), and the ratio of trans-3'-hydroxycotinine to cotinine (another indicator of CYP2A6 activity) were measured. RESULTS: The clearances of nicotine and cotinine, the clearance of nicotine to cotinine, and the trans-3'-hydroxycotinine/cotinine ratio were significantly higher in women than in men (nicotine clearance, 15.6 +/- 4.3 mL.min(-1).kg(-1) in men versus 18.8 +/- 6.6 mL.min(-1).kg(-1) in women; P < .001); they were also higher among women taking oral contraceptives than in those who were not taking oral contraceptives (nicotine clearance, 22.5 +/- 6.6 mL.min(-1).kg(-1) in women taking oral contraceptives versus 17.6 +/- 6.1 mL.min(-1).kg(-1) in those who were not; P < .05). Women who were menopausal or postmenopausal were not different from men. Among oral contraceptive users, nicotine metabolism was accelerated among those taking combined and estrogen-only contraceptives but not progesterone-only contraceptives. CONCLUSIONS: Sex hormones influence nicotine metabolism. Nicotine and cotinine metabolism is faster in women than in men and is faster in women taking oral contraceptives compared with those who are not. Accelerated nicotine metabolism appears to be a result of estrogen. Sex-related differences in nicotine clearance could affect smoking behaviors, as well as response to nicotine medications, and could be a marker for altered metabolism of nicotine-derived carcinogens.

Adolescent↗
PubMed2006

CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.

BACKGROUND AND OBJECTIVE: The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously. METHODS: Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12. RESULTS: On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1. CONCLUSIONS: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

Adolescent↗
PubMed2006

Financial burden of tobacco use: an employer's perspective.

To assist in determining whether employer-sponsored smoking cessation programs can be justified on cost-effectiveness grounds, a review was performed to examine the costs imposed on employers by smoking and the extent to which employers can recover those costs through successful smoking cessation programs. The magnitude of the costs (or cost savings) imposed by employee tobacco use depends on workplace factors, including medical coverage (before and after retirement), disability and life insurance benefits, level of exposure to workplace pollutants associated with smoking-related diseases, employee turnover rate, current smoke-free area policy, smoking breaks policy, cost of providing smoking areas, and type of retirement pension plan.

Air Pollution, Indoor↗
PubMed2006

Tailoring nicotine replacement therapy: rationale and potential approaches.

Nicotine replacement therapy (NRT) is an effective treatment for smoking cessation, but as with all such pharmacotherapies, the majority of smokers who use NRT products do not stop smoking or remain abstinent long term. Treatment outcome is affected by a range of individual-specific factors, as well as the pharmacokinetic profile of each NRT formulation. This has led to speculation that abstinence rates could be improved if NRT treatments were individually tailored to best match each individual's needs and preferences. There are also populations for whom special product and dosage considerations are warranted to maximise treatment safety.This paper reviews the rationale for NRT treatment, standard dose recommendations and recommendations for how to best match NRT treatment to the specific needs of individual smokers. We also review emerging evidence that genetic profiling may one day be a useful consideration for tailoring NRT treatment.

Animals↗
PubMed2005

Heritability of plasma sex hormones and hormone binding globulin in adult male twins.

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.

Aged↗
PubMed2005

Validity of retrospective assessments of nicotine dependence: a preliminary report.

Information about levels of nicotine dependence in ex-smokers when they smoked, or in current smokers at an earlier date, is useful for clinical and research purposes. To estimate the accuracy of retrospective reports of dependence, 28 individuals who completed either the Fagerström Tolerance Questionnaire (FTQ) or Fagerström Test for Nicotine Dependence (FTND) in smoking cessation trials conducted 5 to 12 years earlier were asked to respond again to the same questions, thinking back to their smoking behavior just prior to their on-study quit attempt. Concordance and Kappa values for the items ranged from 50.0% to 95.0% and 0.00 to 0.92, respectively. The mean difference between the baseline and follow-up total scale scores was 0.05 for the FTQ and 0.38 for the FTND, and the correlation between these assessments was 0.62 for the FTQ (p<0.005) and 0.72 for the FTND (p<0.05). These preliminary results suggest that retrospectively assessed FTQ/FTND scale scores have acceptable reliability.

Adult↗
PubMed2005

Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.

BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition.

Alcohol Drinking↗
PubMed2005

Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.

To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1x2, *2, *4, *7, *9 and *12). Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI)=44.7-70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9-71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified.

Adolescent↗
PubMed2005

Apolipoprotein E epsilon4 and change in cognitive functioning in community-dwelling older adults.

The relationship between apolipoprotein E (APOE) epsilon4 and change in cognition was examined in older men (n = 247; age = 75.0 +/- 3.5 years) and women (n = 79; age = 70.8 +/- 4.9 years) free of history of stroke. Participants were examined again 4.0 +/- 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4 genotype. Men with epsilon4 showed greater decline in some measures of executive function and verbal memory compared to those without epsilon4; women with epsilon4 showed greater decline in Trail Making test performance relative to women without the allele. A significant gender x APOE epsilon4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE epsilon4 is associated with cognitive decline differently in older adult men and women.

Aged↗
PubMed2005

Smoking cessation treatment: pharmacogenetic assessment.

This review focuses on the current status and future directions of pharmacogenetics research into responses to treatments for nicotine dependence and smoking cessation. Research remains in its infancy and, although the potential for individualized treatment tailored to genotype is promising, there are practical, ethical and social considerations that must be addressed before such research is translated into clinical practice. In particular, future studies that need to be conducted before such research is translated into clinical practice and potential limitations and barriers to this translation are described.

Genotype↗