Dataset Information

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

ABSTRACT:

Context

Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.

Objective

To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.

Data sources

Primary data.

Study selection

Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.

Data extraction

Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.

Data synthesis

Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).

Conclusion

These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

SUBMITTER: Hartz SM

PROVIDER: S-EPMC3482121 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

Hartz Sarah M SM Short Susan E SE Saccone Nancy L NL Culverhouse Robert R Chen LiShiun L Schwantes-An Tae-Hwi TH Coon Hilary H Han Younghun Y Stephens Sarah H SH Sun Juzhong J Chen Xiangning X Ducci Francesca F Dueker Nicole N Franceschini Nora N Frank Josef J Geller Frank F Gubjartsson Daniel D Hansel Nadia N NN Jiang Chenhui C Keskitalo-Vuokko Kaisu K Liu Zhen Z Lyytikäinen Leo-Pekka LP Michel Martha M Rawal Rajesh R Rosenberger Albert A Scheet Paul P Shaffer John R JR Teumer Alexander A Thompson John R JR Vink Jacqueline M JM Vogelzangs Nicole N Wenzlaff Angela S AS Wheeler William W Xiao Xiangjun X Yang Bao-Zhu BZ Aggen Steven H SH Balmforth Anthony J AJ Baumeister Sebastian E SE Beaty Terri T Bennett Siiri S Bergen Andrew W AW Boyd Heather A HA Broms Ulla U Campbell Harry H Chatterjee Nilanjan N Chen Jingchun J Cheng Yu-Ching YC Cichon Sven S Couper David D Cucca Francesco F Dick Danielle M DM Foroud Tatiana T Furberg Helena H Giegling Ina I Gu Fangyi F Hall Alistair S AS Hällfors Jenni J Han Shizhong S Hartmann Annette M AM Hayward Caroline C Heikkilä Kauko K Hewitt John K JK Hottenga Jouke Jan JJ Jensen Majken K MK Jousilahti Pekka P Kaakinen Marika M Kittner Steven J SJ Konte Bettina B Korhonen Tellervo T Landi Maria-Teresa MT Laatikainen Tiina T Leppert Mark M Levy Steven M SM Mathias Rasika A RA McNeil Daniel W DW Medland Sarah E SE Montgomery Grant W GW Muley Thomas T Murray Tanda T Nauck Matthias M North Kari K Pergadia Michele M Polasek Ozren O Ramos Erin M EM Ripatti Samuli S Risch Angela A Ruczinski Ingo I Rudan Igor I Salomaa Veikko V Schlessinger David D Styrkársdóttir Unnur U Terracciano Antonio A Uda Manuela M Willemsen Gonneke G Wu Xifeng X Abecasis Goncalo G Barnes Kathleen K Bickeböller Heike H Boerwinkle Eric E Boomsma Dorret I DI Caporaso Neil N Duan Jubao J Edenberg Howard J HJ Francks Clyde C Gejman Pablo V PV Gelernter Joel J Grabe Hans Jörgen HJ Hops Hyman H Jarvelin Marjo-Riitta MR Viikari Jorma J Kähönen Mika M Kendler Kenneth S KS Lehtimäki Terho T Levinson Douglas F DF Marazita Mary L ML Marchini Jonathan J Melbye Mads M Mitchell Braxton D BD Murray Jeffrey C JC Nöthen Markus M MM Penninx Brenda W BW Raitakari Olli O Rietschel Marcella M Rujescu Dan D Samani Nilesh J NJ Sanders Alan R AR Schwartz Ann G AG Shete Sanjay S Shi Jianxin J Spitz Margaret M Stefansson Kari K Swan Gary E GE Thorgeirsson Thorgeir T Völzke Henry H Wei Qingyi Q Wichmann H-Erich HE Amos Christopher I CI Breslau Naomi N Cannon Dale S DS Ehringer Marissa M Grucza Richard R Hatsukami Dorothy D Heath Andrew A Johnson Eric O EO Kaprio Jaakko J Madden Pamela P Martin Nicholas G NG Stevens Victoria L VL Stitzel Jerry A JA Weiss Robert B RB Kraft Peter P Bierut Laura J LJ

Archives of general psychiatry 20120801 8

<h4>Context</h4>Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.<h4>Objective</h4>To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.<h4>Data sources</h4>Primary data.<h4>Study selection</h4>Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.<h4>Data extraction</h4>Uniform statistical analy ...[more]

PMID: 22868939

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Project description:CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.

Project description:Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

Project description:BackgroundRecent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not.MethodsMeta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium.ResultsSmoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10-10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype.ConclusionWe demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Dataset Information

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

Context

Objective

Data sources

Study selection

Data extraction

Data synthesis

Conclusion

Publications

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

Similar Datasets

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