Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma.

BACKGROUND: Childhood asthma is characterized by chronic airway inflammation. Integrative genomic analysis of airway inflammation on genetic and protein level may help to unravel mechanisms of childhood asthma. We aimed to employ an integrative genomic approach investigating inflammation markers on DNA, mRNA, and protein level at preschool age in relationship to asthma development. METHODS: In a prospective study, 252 preschool children (202 recurrent wheezers, 50 controls) from the Asthma DEtection and Monitoring (ADEM) study were followed until the age of six. Genetic variants, mRNA expression in peripheral blood mononuclear cells, and protein levels in exhaled breath condensate for intercellular adhesion molecule 1 (ICAM1), interleukin (IL)4, IL8, IL10, IL13, and tumor necrosis factor α were analyzed at preschool age. At six years of age, a classification (healthy, transient wheeze, or asthma) was based on symptoms, lung function, and medication use. RESULTS: The ICAM1 rs5498 A allele was positively associated with asthma development (p = 0.02) and ICAM1 gene expression (p = 0.01). ICAM1 gene expression was positively associated with exhaled levels of soluble ICAM1 (p = 0.04) which in turn was positively associated with asthma development (p = 0.01). Furthermore, rs1800872 and rs1800896 in IL10 were associated with altered IL10 mRNA expression (p < 0.01). Exhaled levels of IL4, IL10, and IL13 were positively associated with asthma development (p < 0.01). CONCLUSIONS: In this unique prospective study, we demonstrated that ICAM1 is associated with asthma development on DNA, mRNA, and protein level. Thus, ICAM1 is likely to be involved in the development of childhood asthma.

Knowledge, attitudes and preferences regarding genetic testing for smoking cessation. A cross-sectional survey among Dutch smokers.

Objectives Recent research strongly suggests that genetic variation influences smokers' ability to stop. Therefore, the use of (pharmaco) genetic testing may increase cessation rates. This study aims to assess the intention of smokers concerning undergoing genetic testing for smoking cessation and their knowledge, attitudes and preferences about this subject. Design Online cross-sectional survey. Setting Database internet research company of which every inhabitant of the Netherlands of ≥12 years with an email address and capable of understanding Dutch can become a member. Participants 587 of 711 Dutch smokers aged ≥18 years, daily smokers for ≥5 years and smoke on average ≥10 cigarettes/day (response rate=83%). Primary and secondary outcome measures Smokers' knowledge, attitudes and preferences and their intention to undergo genetic testing for smoking cessation. Results Knowledge on the influence of genetic factors in smoking addiction and cessation was found to be low. Smokers underestimated their chances of having a genetic predisposition and the influence of this on smoking cessation. Participants perceived few disadvantages, some advantages and showed moderate self-efficacy towards undergoing a genetic test and dealing with the results. Smokers were mildly interested in receiving information and participating in genetic testing, especially when offered by their general practitioner (GP). Conclusions For successful implementation of genetic testing for smoking in general practice, several issues should be addressed, such as the knowledge on smoking cessation, genetics and genetic testing (including advantages and disadvantages) and the influence of genetics on smoking addiction and cessation. Furthermore, smokers allocate their GPs a crucial role in the provision of information and the delivery of a genetic test for smoking; however, it is unclear whether GPs will be able and willing to take on this role.

Effectiveness of testing for genetic susceptibility to smoking-related diseases on smoking cessation outcomes: a systematic review and meta-analysis.

OBJECTIVE: To examine whether genetic testing for smoking-related diseases benefits smoking cessation. DATA SOURCES: PubMed, EMBASE, ERIC, PsycINFO, PsychArticles, CiNAHL and socINDEX databases, the search engine Google Scholar, and key-author and reference list searches. Study selection Randomised controlled smoking cessation interventions using genetic testing for smoking-related diseases. DATA EXTRACTION: Consistent with the Cochrane guidelines, two reviewers completed the review process (initial n=139) in three phases, title selection (n=56), abstract selection (n=28) and whole paper selection (n=9). From these nine studies, each reviewer extracted information about outcome measures and statistical and methodological quality. Data synthesis Relevant data were abstracted from included papers and were subsequently subjected to meta-analysis. RESULTS: Interest in genetic testing was relatively high with 60-80% of smokers reporting to be interested. The authors observed positive short-term effects on risk perception, motivation to quit smoking and smoking cessation, but these effects fade at longer follow-ups. Importantly, the authors did not find any evidence of adverse effect of testing negative on the risk-predisposing gene. CONCLUSIONS: This systematic review does not provide solid evidence for the proposed beneficial effects of genetic testing for smoking-related diseases on smoking cessation, but does suggest the presence of an immediate motivational effect, such that genetic testing resulted in higher risk perception and more motivation to quit smoking.

Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation.

AIMS: We investigated whether variants in the serotonin transporter gene (SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline). DESIGN: Pharmacogenetic (secondary) analysis of a randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation. SETTING: Single-centre study, Maastricht University, the Netherlands. PARTICIPANTS: A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial. MEASUREMENTS: Subjects were genotyped for three functional variants in SLC6A4 (5-HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4-12, 4-26 and 4-52. Secondary outcome measures included 7-day point prevalence abstinence at weeks 4, 12, 26 and 52. FINDINGS: Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01-2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI =1.21-3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02-3.56, P = 0.04). Similar results were found for point prevalence abstinence. CONCLUSIONS: Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes.

Are smokers interested in genetic testing for smoking addiction? A socio-cognitive approach.

Genetic advances have made genetically tailored smoking cessation treatments possible. In this study, we examined whether smokers are interested in undergoing a genetic test to identify their genetic susceptibility to nicotine addiction. In addition, we aimed to identify socio-cognitive determinants of smokers' intention to undergo genetic testing. Following the protection motivation theory (PMT), we assessed the following constructs using an online survey among 587 smokers: threat appraisal (i.e. susceptibility and severity), fear, coping appraisal (i.e. response efficacy and self-efficacy), response costs and intention. In addition, knowledge, social norms and information-seeking behaviour were measured. Mean intention rates were 2.57 on a 5-point scale. Intention was significantly associated with threat appraisal and coping appraisal, as predicted by the PMT. Fear of the outcome was negatively associated with the intention to undergo genetic testing, but response costs, knowledge and social influence were not. Intention to undergo genetic testing in turn was positively related to seeking information about genetic testing and genetically tailored smoking cessation treatments. Smokers seem ambivalent or 'on the fence' with regard to undergoing a genetic test for smoking addiction. Socio-cognitive concepts such as susceptibility, severity, response efficacy and self-efficacy may be used to inform or educate smokers about the value of genetically tailored smoking cessation treatments.

Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases.

Tobacco smoking continues to be the major preventable cause of premature morbidity and mortality throughout the world. Recent research strongly suggests that genetic background is associated with several aspects of smoking (e.g. initiation, maintenance, cessation, number of cigarettes smoked, indicators of nicotine dependence (ND) and nicotine withdrawal). Variations in two broad classes of genes have been shown to influence smoking: (1) genes that may influence the response to nicotine (e.g. nicotine metabolism, nicotinic receptors) and (2) genes that may predispose to addictive behaviour via their effects on key neurotransmitter pathways (e.g. dopamine, serotonin and opioid). Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, smoking cessation rates might be increased by determining which treatment would be most effective based on the smoker's genetic background. This is expected to result in a more efficient use of smoking cessation therapies, increased cessation rates and ultimately, in reduced deaths from smoking. Until now, most research on the influence of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) and the antidepressant bupropion. Overall, genotypes associated with increased dopamine availability seem to predict a better response to bupropion, while smokers with genotypes associated with reduced dopamine levels probably achieve better quit rates with NRT. A decreased metabolism for the drug used (e.g. bupropion or NRT), results in increased cessation rates as well. Furthermore, smokers with reduced dopaminergic and nicotinic receptor activity variants may experience greater benefit from nicotine spray, while smokers with increased activity variants in the opioid receptor may have greater success with transdermal patches. Thus it seems that genetic information may give directions in determining which treatment would be most effective for an individual smoker. However, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.