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Laura J Bierut - One of the best experts on this subject based on the ideXlab platform.
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variants in the chrna5 chrna3 CHRNB4 region of chromosome 15 predict gastrointestinal adverse events in the transdisciplinary tobacco use research center smoking cessation trial
Nicotine & Tobacco Research, 2019Co-Authors: Robert Culverhouse, Lishiun Chen, Nancy L Saccone, Timothy B Baker, Megan E Piper, Laura J BierutAbstract:INTRODUCTION: Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step towards this goal. In 2012 King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events, and to extend the analyses to adherence and smoking cessation. METHODS: The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multi-armed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy (NRT) that included 985 genotyped European-ancestry participants. We evaluated relations between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% of the TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. CONCLUSIONS: Variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. IMPLICATIONS: The fact that our findings from the TTURC smoking cessation trial, support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.
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genomics and personalized medicine chrna5 chrna3 CHRNB4 and smoking cessation treatment
Journal of Food and Drug Analysis, 2013Co-Authors: Lishiun Chen, Laura J BierutAbstract:Abstract Cigarette smoking is highly addictive, and modern genetic research has identified robust genetic influences on nicotine dependence. An important step in translating these genetic findings is to identify the genetic factors affecting smoking cessation in order to enhance current smoking cessation treatments. We review the significance of variants in the nicotinic receptor gene cluster ( CHRNA5–CHRNA3–CHRNB4 ) in the prediction of smoking quantity, smoking cessation, and response to cessation medication in multiple studies of smoking cessation. Three common haplotypes (low-risk, intermediate-risk, and high-risk) in the CHRNA5–CHRNA3–CHRNB4 region are defined by rs16969968 and rs680244. The genetic variants in the CHRNA5–CHRNA3–CHRNB4 region that predict nicotine dependence also predicted a later age of smoking cessation in a community-based sample. In a smoking cessation trial, these variants predicted abstinence at the end of treatment in individuals receiving placebo medication, but not among individuals receiving active medication. Pharmacological treatments moderate the genetic risk in affecting cessation success. These pharmacogenetic interactions have been reproduced by a recent meta-analysis of smoking cessation trials. The number needed to treat was four for smokers with the high-risk haplotype, seven for smokers with the intermediate-risk haplotype, and > 1000 for smokers with the low-risk haplotype. The wide variation in number needed to treat between smokers with different haplotypes supports the notion that personalized smoking cessation intervention based upon genotype could meaningfully increase the efficiency of such treatment. In summary, variants in the CHRNA5–CHRNA3–CHRNB4 region identify individuals at increased risk of cessation failure, and this increased risk can be ameliorated by cessation pharmacotherapy.
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Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials
Neuropsychopharmacology, 2012Co-Authors: David P King, Laura J Bierut, Jaakko Kaprio, Sara Paciga, Eve Pickering, Neal L Benowitz, David V Conti, Caryn Lerman, Peter W ParkAbstract:Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2 , CHRNA5 , and CHRNA4 ) (OR=1.76; 95% CI: 1.23–2.52) ( p
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smoking cessation pharmacogenetics analysis of varenicline and bupropion in placebo controlled clinical trials
Neuropsychopharmacology, 2012Co-Authors: David P King, Laura J Bierut, Jaakko Kaprio, Sara Paciga, Neal L Benowitz, David V Conti, Caryn Lerman, Eve H Pickering, Peter W ParkAbstract:Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
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Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans
Genes Brain and Behavior, 2010Co-Authors: Nancy L Saccone, Dorothy Hatsukami, Richard A Grucza, Naomi Breslau, Eric O. Johnson, Tae-hwi Schwantes-an, John P. Rice, Alison Goate, Laura J BierutAbstract:Several independent studies show that the chromosome 15q25.1 region, which contains the CHRNA5–CHRNA3–CHRNB4 gene cluster, harbors variants strongly associated with nicotine dependence, other smoking behaviors, lung cancer and chronic obstructive pulmonary disease. We investigated whether variants in other cholinergic nicotinic receptor subunit (CHRN) genes affect the risk of nicotine dependence in a new sample of African Americans (AAs) (N = 710). We also analyzed this AA sample together with a European American (EA) sample (N = 2062, 1608 of which have been previously studied), allowing for differing effects in the two populations. Cases are current nicotine-dependent smokers and controls are non-dependent smokers. Variants in or near CHRND–CHRNG, CHRNA7 and CHRNA10 show modest association with nicotine dependence risk in the AA sample. In addition, CHRNA4, CHRNB3–CHRNA6 and CHRNB1 show association in at least one population. CHRNG and CHRNA4 harbor single nucleotide polymorphisms (SNPs) that have opposite directions of effect in the two populations. In each of the population samples, these loci substantially increase the trait variation explained, although no loci meet Bonferroni-corrected significance in the AA sample alone. The trait variation explained by three key associated SNPs in CHRNA5–CHRNA3–CHRNB4 is 1.9% in EAs and also 1.9% in AAs; this increases to 4.5% in EAs and 7.3% in AAs when we add six variants representing associations at other CHRN genes. Multiple nicotinic receptor subunit genes outside chromosome 15q25 are likely to be important in the biological processes and development of nicotine dependence, and some of these risks may be shared across diverse populations.
Jaakko Kaprio - One of the best experts on this subject based on the ideXlab platform.
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smoking cessation pharmacogenetics analysis of varenicline and bupropion in placebo controlled clinical trials
Neuropsychopharmacology, 2012Co-Authors: David P King, Laura J Bierut, Jaakko Kaprio, Sara Paciga, Neal L Benowitz, David V Conti, Caryn Lerman, Eve H Pickering, Peter W ParkAbstract:Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
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Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials
Neuropsychopharmacology, 2012Co-Authors: David P King, Laura J Bierut, Jaakko Kaprio, Sara Paciga, Eve Pickering, Neal L Benowitz, David V Conti, Caryn Lerman, Peter W ParkAbstract:Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2 , CHRNA5 , and CHRNA4 ) (OR=1.76; 95% CI: 1.23–2.52) ( p
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Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15
Human Molecular Genetics, 2009Co-Authors: Kaisu Keskitalo, Ulla Broms, Ida Surakka, Samuli Ripatti, Markus Perola, Arpo Aromaa, Janne Pitkäniemi, Markku Heliövaara, Leena Peltonen, Jaakko KaprioAbstract:A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30–75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R 2 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
Danielle M Dick - One of the best experts on this subject based on the ideXlab platform.
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variants located upstream of CHRNB4 on chromosome 15q25 1 are associated with age at onset of daily smoking and habitual smoking
PLOS ONE, 2012Co-Authors: Manav Kapoor, Jen-chyong Wang, Andrew Brooks, John P Budde, Anthony L. Hinrichs, Sarah Bertelsen, Arpana Agrawal, Kathleen K Bucholz, David B Chorlian, Danielle M DickAbstract:Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28
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Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.
PLoS ONE, 2012Co-Authors: Manav Kapoor, Jen-chyong Wang, Andrew Brooks, John P Budde, Anthony L. Hinrichs, Sarah Bertelsen, Arpana Agrawal, Kathleen K Bucholz, David B Chorlian, Danielle M DickAbstract:Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28
Arpo Aromaa - One of the best experts on this subject based on the ideXlab platform.
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association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes chrna3 chrna5 CHRNB4 on chromosome 15
Human Molecular Genetics, 2009Co-Authors: Kaisu Keskitalo, Ulla Broms, Ida Surakka, Samuli Ripatti, Markus Perola, Janne Pitkäniemi, Markku Heliövaara, Leena Peltonen, Arpo AromaaAbstract:A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30–75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R 2 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
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Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15
Human Molecular Genetics, 2009Co-Authors: Kaisu Keskitalo, Ulla Broms, Ida Surakka, Samuli Ripatti, Markus Perola, Arpo Aromaa, Janne Pitkäniemi, Markku Heliövaara, Leena Peltonen, Jaakko KaprioAbstract:A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30–75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R 2 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
Joe Henry Steinbach - One of the best experts on this subject based on the ideXlab platform.
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functional characterization improves associations between rare non synonymous variants in CHRNB4 and smoking behavior
PLOS ONE, 2014Co-Authors: Gabe Haller, Alison Goate, Caroline Esch, Simon Hsu, Joe Henry SteinbachAbstract:Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (<5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal α3 or α4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration-response curves and qRT-PCR, western blots and cell-surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (β = -0.67, r2 = 0.017, P = 2 × 10(-4)) or by response to low nicotine (β = -0.29, r2 = 0.02, P = 6 × 10(-5)) when variants are expressed with the α3 subunit. In contrast, there is no significant association when carrier status is unweighted (β = -0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence.
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Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior.
PLoS ONE, 2014Co-Authors: Gabe Haller, Alison Goate, Caroline Esch, Simon Hsu, Joe Henry SteinbachAbstract:Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (
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Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence
Human Molecular Genetics, 2011Co-Authors: Gabe Haller, Todd E. Druley, Robi D. Mitra, Naomi Breslau, Joe Henry Steinbach, Francesco Vallania, Ping Li, Eric O. Johnson, Dorothy HatsukamiAbstract:Genome-wide association studies have identified common variation in the CHRNA5–CHRNA3–CHRNB4 and CHRNA6–CHRNB3 gene clusters that contribute to nicotine dependence. However, the role of rare variation in risk for nicotine dependence in these nicotinic receptor genes has not been studied. We undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes in African American and European American nicotine-dependent smokers and smokers without symptoms of dependence. Carrier status of individuals harboring rare missense variants at conserved sites in each of these genes was then compared in cases and controls to test for an association with nicotine dependence. Missense variants at conserved residues in CHRNB4 are associated with lower risk for nicotine dependence in African Americans and European Americans (AA P 5 0.0025, odds-ratio (OR) 5 0.31, 95% confidence-interval (CI) 5 0.31‐0.72; EA P 5 0.023, OR 5 0.69, 95% CI 5 0.50‐0.95). Furthermore, these individuals were found to smoke fewer cigarettes per day than non-carriers (AA P 5 6.6 3 10 25 ,E AP 5 0.021). Given the possibility of stochastic differences in rare allele frequencies between groups replication of this association is necessary to confirm these findings. The functional effects of the two CHRNB4 variants contributing most to this association (T375I and T91I) and a missense variant in CHRNA3 (R37H) in strong linkage disequilibrium with T91I were examined in vitro. The minor allele of each polymorphism increased cellular response to nicotine (T375I P 5 0.01, T91I P 5 0.02, R37H P 5 0.003), but the largest effect on in vitro receptor activity was seen in the presence of both CHRNB4 T91I and CHRNA3 R37H (P 5 2 3 10 26 ).