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Nancy L Saccone - 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, 2020Co-Authors: Robert Culverhouse, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, Yinjiao Ma, 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 toward 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 multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. 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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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, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, 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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distinct loci in the chrna5 CHRNA3 chrnb4 gene cluster are associated with onset of regular smoking
Genetic Epidemiology, 2013Co-Authors: Sarah H Stephens, Nancy L Saccone, Naomi Breslau, Nicole R Hoft, Robin C Corley, Christian J Hopfer, John K Hewitt, Sarah M Hartz, Hilary Coon, Xiangning ChenAbstract:Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
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Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.
Genetic Epidemiology, 2013Co-Authors: Sarah H Stephens, Nancy L Saccone, Naomi Breslau, Nicole R Hoft, Robin C Corley, Christian J Hopfer, John K Hewitt, Sarah M Hartz, Hilary Coon, Xiangning ChenAbstract:Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
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interplay of genetic risk factors chrna5 CHRNA3 chrnb4 and cessation treatments in smoking cessation success
American Journal of Psychiatry, 2012Co-Authors: Lishiun Chen, Nancy L Saccone, Naomi Breslau, Eric O. Johnson, Megan E Piper, Timothy B Baker, Dale S Cannon, Kimberly F Doheny, Stephanie M Gogarten, Jen C WangAbstract:When smokers were separated by their nicotinic receptor gene variants, those with the low-risk genotype responded equally well to pharmacological treatments, including both nicotine replacement and bupropion, and nonpharmacological therapies. Those with the high-risk genotype, as identified by DNA sequencing, responded only to pharmacological treatments. Clinicians advising patients on smoking cessation can suspect genetic risk on the basis of early onset of heavy smoking and direct those smokers specifically to pharmacological treatments.
Robert Culverhouse - 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, 2020Co-Authors: Robert Culverhouse, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, Yinjiao Ma, 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 toward 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 multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. 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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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, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, 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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the chrna5 CHRNA3 chrnb4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in african americans and in european americans
Cancer Research, 2009Co-Authors: Nancy L Saccone, Scott F Saccone, Weimin Duan, Naomi Breslau, Richard A Grucza, Eric O. Johnson, Dorothy K. Hatsukami, John P Budde, Jen C Wang, Robert CulverhouseAbstract:Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample ( N = 710) and in a European-American sample ( N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [ P = 4.49 × 10 −8 ; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only ( P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only ( P = 4.14 × 10 −7 ; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency ≤ 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5 . The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]
T V Victorova - One of the best experts on this subject based on the ideXlab platform.
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Association of the nicotine and cigarette smoke toxicants metabolic (CHRNA3/5, CYP2A6, NQO1) and DNA repair genes (XRCC1, XRCC3, XPC, XPA) with chronic obstructive pulmonary disease
Molecular Biology, 2020Co-Authors: G F Korytina, L Z Akhmadishina, O V Kochetova, T V VictorovaAbstract:Abstract The contribution of the polymorphic markers of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, XRCC3, XPD, XPA genes to chronic obstructive pulmonary disease has been assessed. For this purpose, analysis of the gene polymorphisms in case/control groups in Tatar population has been performed. The CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24), CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) were associated with significantly high risk of chronic obstructive pulmonary disease in recessive model. The disease risk was higher in homozygous carriers of normal allele of CYP2A6 (del) (P = 0.00001, OR = 2.77). Analysis showed an association of the NQO1 (rs1131341), XRCC1 (rs25487), XRCC3 (rs861539), XPC (rs2228001) and XPA (rs1800975) (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54 and P = 0.007, OR = 0.74) in additive model with chronic obstructive pulmonary disease. We found a significant gene-by-environment interaction of smoking status and XPA (rs1800975) (Pinteract = 0.002); rs16969968, rs1051730 of CHRNA3/5 genes were significantly associated with chronic obstructive pulmonary disease only in smokers. The relationship between the CYP2A6(CYP2A6*4) and smoking pack-years was found (P = 0.0019). The TT genotype of XRCC3 (rs861539) were associated with decreased of lung function parameters: vital capacity % (P = 0.0487), forced vital capacity (%) (P = 0.0032) and forced expiratory volume in 1 s (%) (P = 0.02). The relationship between the XPA (rs1800975) and forced expiratory volume in 1 s (%) (P = 0.0028) was found.
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association of genes involved in nicotine and tobacco smoke toxicant metabolism CHRNA3 5 cyp2a6 and nqo1 and dna repair xrcc1 xrcc3 xpc and xpa with chronic obstructive pulmonary disease
Molecular Biology, 2014Co-Authors: G F Korytina, L Z Akhmadishina, O V Kochetova, Yu V Burduk, Y G Aznabaeva, Sh Z Zagidullin, T V VictorovaAbstract:Polymorphisms of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, CRCC3, XPD, and XPA genes were tested for association with the development and progression of chronic obstructive pulmonary disease (COPD) in ethnic Tatars. CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24) and CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) polymorphisms were associated with COPD development in the recessive model. The nondeletion variant of CYP2A6 (del) was associated with COPD risk (P = 0.00001, OR = 2.77). NQO1 (rs113341), XRCC1 (rs25487), XRCC3 (rs86539), XPC (rs2228001), and XPA (rs1800975) were associated with COPD in the additive model (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54; and P = 0.007, OR = 0.74, respectively). A gene-by-environment interaction was observed for XPA (rs1800975) and the smoking status (P interact = 0.002), and the rs16969968 and rs1051730 polymorphisms of the CHRNA3/5 gene cluster showed an association with COPD only in smokers. Carriers of the CYP2A6 deletion (CYP2A6*4) had a lower smoking index (P = 0.0019). XRCC3 (rs861539) genotype TT was characterized by lower indices of pulmonary function, including vital capacity (VC) (P = 0.0487), forced vital capacity (FVC) (P = 0.0032), and forced expiratory volume in 1 second (FEV1) (P = 0.02). FVC was found to depend on the genotype at XPA (rs1800975) (P = 0.0028).
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Association of genes involved in nicotine and tobacco smoke toxicant metabolism (CHRNA3/5, CYP2A6, and NQO1) and DNA repair (XRCC1, XRCC3, XPC, and XPA) with chronic obstructive pulmonary disease
Molecular Biology, 2014Co-Authors: G F Korytina, L Z Akhmadishina, O V Kochetova, Yu V Burduk, Y G Aznabaeva, Sh Z Zagidullin, T V VictorovaAbstract:Polymorphisms of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, CRCC3, XPD, and XPA genes were tested for association with the development and progression of chronic obstructive pulmonary disease (COPD) in ethnic Tatars. CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24) and CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) polymorphisms were associated with COPD development in the recessive model. The nondeletion variant of CYP2A6 (del) was associated with COPD risk (P = 0.00001, OR = 2.77). NQO1 (rs113341), XRCC1 (rs25487), XRCC3 (rs86539), XPC (rs2228001), and XPA (rs1800975) were associated with COPD in the additive model (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54; and P = 0.007, OR = 0.74, respectively). A gene-by-environment interaction was observed for XPA (rs1800975) and the smoking status (P interact = 0.002), and the rs16969968 and rs1051730 polymorphisms of the CHRNA3/5 gene cluster showed an association with COPD only in smokers. Carriers of the CYP2A6 deletion (CYP2A6*4) had a lower smoking index (P = 0.0019). XRCC3 (rs861539) genotype TT was characterized by lower indices of pulmonary function, including vital capacity (VC) (P = 0.0487), forced vital capacity (FVC) (P = 0.0032), and forced expiratory volume in 1 second (FEV1) (P = 0.02). FVC was found to depend on the genotype at XPA (rs1800975) (P = 0.0028).
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association of the nicotine and cigarette smoke toxicants metabolic CHRNA3 5 cyp2a6 nqo1 and dna repair genes xrcc1 xrcc3 xpc xpa with chronic obstructive pulmonary disease
Molecular Biology, 2014Co-Authors: G F Korytina, L Z Akhmadishina, O V Kochetova, T V VictorovaAbstract:Abstract The contribution of the polymorphic markers of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, XRCC3, XPD, XPA genes to chronic obstructive pulmonary disease has been assessed. For this purpose, analysis of the gene polymorphisms in case/control groups in Tatar population has been performed. The CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24), CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) were associated with significantly high risk of chronic obstructive pulmonary disease in recessive model. The disease risk was higher in homozygous carriers of normal allele of CYP2A6 (del) (P = 0.00001, OR = 2.77). Analysis showed an association of the NQO1 (rs1131341), XRCC1 (rs25487), XRCC3 (rs861539), XPC (rs2228001) and XPA (rs1800975) (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54 and P = 0.007, OR = 0.74) in additive model with chronic obstructive pulmonary disease. We found a significant gene-by-environment interaction of smoking status and XPA (rs1800975) (Pinteract = 0.002); rs16969968, rs1051730 of CHRNA3/5 genes were significantly associated with chronic obstructive pulmonary disease only in smokers. The relationship between the CYP2A6(CYP2A6*4) and smoking pack-years was found (P = 0.0019). The TT genotype of XRCC3 (rs861539) were associated with decreased of lung function parameters: vital capacity % (P = 0.0487), forced vital capacity (%) (P = 0.0032) and forced expiratory volume in 1 s (%) (P = 0.02). The relationship between the XPA (rs1800975) and forced expiratory volume in 1 s (%) (P = 0.0028) was found.
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, 2020Co-Authors: Robert Culverhouse, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, Yinjiao Ma, 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 toward 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 multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. 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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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, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, 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.
Lishiun Chen - 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, 2020Co-Authors: Robert Culverhouse, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, Yinjiao Ma, 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 toward 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 multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. 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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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, Nancy L Saccone, Lishiun Chen, Megan E Piper, Timothy B Baker, 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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interplay of genetic risk factors chrna5 CHRNA3 chrnb4 and cessation treatments in smoking cessation success
American Journal of Psychiatry, 2012Co-Authors: Lishiun Chen, Nancy L Saccone, Naomi Breslau, Eric O. Johnson, Megan E Piper, Timothy B Baker, Dale S Cannon, Kimberly F Doheny, Stephanie M Gogarten, Jen C WangAbstract:When smokers were separated by their nicotinic receptor gene variants, those with the low-risk genotype responded equally well to pharmacological treatments, including both nicotine replacement and bupropion, and nonpharmacological therapies. Those with the high-risk genotype, as identified by DNA sequencing, responded only to pharmacological treatments. Clinicians advising patients on smoking cessation can suspect genetic risk on the basis of early onset of heavy smoking and direct those smokers specifically to pharmacological treatments.