PubMed Health⌕ Search

Biomedical subjects

Robert Walton

Publications and source records attributed to Robert Walton.

14 recordsLinked to original sources
PubMed2006

Determinants of the rate of nicotine metabolism and effects on smoking behavior.

BACKGROUND: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. METHODS: We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. RESULTS: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). CONCLUSION: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Adult↗
PubMed2004

The genetic basis for smoking behavior: a systematic review and meta-analysis.

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.

Genetic Predisposition to Disease↗
PubMed2004

Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1.

Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD.

Adolescent↗
PubMed2003

Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC.

Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD patterns across the human MHC by the construction of gene-specific allelic haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found across both common and rare haplotypes, suggesting that haplotype structure is influenced by factors other than genetic drift, including both selection and differential haplotype recombination. Knowledge of haplotype-specific LD in the HLA may explain the apparent discrepant data from previous studies of global LD, help delineate key areas in mapping HLA-associated diseases and, together with recombination data, provide valuable information about a population's demographic history and the selective pressures operating on it.

Alleles↗
PubMed2003

Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms?

OBJECTIVE: Experimental evidence suggests that inappropriate regulation of tumor necrosis factor alpha (TNF alpha) may play a role in the pathogenesis of Behçet's disease (BD). This is supported by recent reports highlighting the efficacy of anti-TNF alpha agents in the treatment of this disease. The TNF gene is encoded in the class III region of the HLA complex adjacent to HLA-B. This genetic proximity to a gene that is already widely implicated in disease susceptibility led us to investigate the association between TNF promoter polymorphisms and susceptibility to BD. METHODS: We studied 133 UK white Caucasoid patients with BD and 354 healthy controls. We attempted to dissect the contribution of individual polymorphisms in this gene-dense region by linkage disequilibrium mapping across 6 adjacent genes. RESULTS: We report a novel association with the TNF promoter allele TNF-1031C. Subsequent analysis identified 2 extended HLA haplotypes associated with BD. One of them contained the previously recognized susceptibility gene HLA-B*51, while the other was defined by HLA-B*5701. Both of these haplotypes contained the TNF promoter polymorphism -1031C, an allele that was associated with disease even in individuals who did not carry either HLA-B*51 or HLA-B*5701. CONCLUSION: The TNF-1031C allele is independently associated with susceptibility to BD in Caucasoid patients. Further studies will be required to determine the functional effects of this polymorphism, its influence in disease pathogenesis, and its role in other ethnic groups.

Behcet Syndrome↗
PubMed2002

No association between functional catechol O-methyl transferase 1947A>G polymorphism and smoking initiation, persistent smoking or smoking cessation.

Nicotine stimulates dopamine release and activates dopaminergic reward neurones in central pathways giving rise to dependence. Catechol O-methyl transferase (COMT) inactivates extraneuronally released dopamine and is present in dopaminergic brain regions. A functional polymorphism (COMT 1947A>G) resulting in increased enzyme activity has been associated with alcoholism and polysubstance abuse. We examined the relationship between the COMT 1947A>G polymorphism and smoking initiation, smoking persistence and smoking cessation. We genotyped 266 current smokers, 270 ex-smokers and 265 lifetime non-smokers (never smokers), matched for age and gender, for the COMT 1947A>G polymorphism. Smoking status was ascertained by self-report. There was no difference in genotype frequencies between never smokers and ever smokers (current + ex-smokers); between non-smokers (never + ex-smokers) and current smokers; or between current smokers and ex-smokers. These data suggest that the COMT 1947A>G polymorphism is not associated with smoking initiation, smoking persistence or smoking cessation.

Adult↗
PubMed2002

Characterization of cytochrome P450 2D6 alleles using the Invader system.

The cytochrome p450 (CYP) superfamily comprises enzymes that play an essential role in the transformation of medically relevant compounds. Accurate genotyping of polymorphisms in members of this family is drawing increasing interest because certain allelic variants may result in either loss of efficacy or toxic accumulation of therapeutic agents. Debrisoquine 4-hydroxylase, or CYP2D6, is among the most widely studied of the CYPs. The complexity of the CYP2D6 genomic region, including pseudogenes, gene deletions, and gene duplications, has offered numerous challenges to developing a genotyping strategy. We describe a comprehensive CYP2D6 genotyping strategy that employs both a PCR/Invader genotyping assay system and an Invader genomic copy number assay The Invader system is a homogeneous, isothermal, highly specific, and robust signal amplification system. Resultsfrom II CYP2D6 assays in an alle frequency study compare well to published allele frequency values for Caucasians. Further, Invader assays provided unambiguous genotyping determinations for 100% of the 171 samples that yielded a visible PCR product on an agarose gel. A copy number assay yielded only one equivocal result in 205 samples. We identified 17 single-copy individuals and 17 three-copy (or more) individuals.

Alleles↗
PubMed2001

New directions in the genetic mechanisms underlying nicotine addiction.

Major advances have been made in understanding nicotine addiction and smoking behaviour in recent years. In particular, evidence for the relative importance of genetic and environmental effects on smoking initiation and persistence has emerged from behaviour genetic studies. These data have supported evidence from molecular genetic studies for the role of particular candidate genes in tobacco dependence. Studies of the personality correlates of smoking behaviour suggest that these factors mediate the association between genetics and smoking initiation, while learning models of nicotine addiction suggest a role for dopaminergic genes in facilitating neuroadaptations associated with smoking persistence and development of nicotine dependence. Integrating these different avenues of research represents one of the most interesting and potentially fruitful ventures in the treatment of tobacco dependence.

Journal Article↗
PubMedDate not supplied

Zyban for smoking cessation in a general practice setting: the response to an invitation to make a quit attempt.

The objective of this study was to assess the feasibility and success of Zyban as part of a moderately supported smoking cessation programme within UK general practice. Treatment was offered to 479 moderately dependent smokers (smoking 15 or more cigarettes per day) who had never used Zyban, and who had taken part in a previous NRT trial (the PATCH study). Main outcome measures were point prevalence and continuous abstinence from smoking at 6 and at 12 months. Two hundred and forty were excluded because of medical reasons or prescribing contraindication. Of the remainder (n=239) only 54 (23%) made an active quit attempt. Thirty percent (16/54) were abstinent at six months, and 22% (12/54) at 12 months (biochemically validated point prevalence rates). Age, socio-economic status, nicotine dependence, and genetic profile appeared to have little impact on success rates, but male quit-attempters were significantly more successful than female (40% vs. 10% at 12 months, p<0.05). In conclusion, a real-world smoking cessation programme using Zyban with moderate support within a general practice setting may achieve satisfactory quit rates without widening existing disparities in cessation.

Adult↗