Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15

Keskitalo, Kaisu; Broms, Ulla; Heliövaara, Markku; Ripatti, Samuli; Surakka, Ida; Perola, Markus; Pitkäniemi, Janne; Peltonen, Leena; Aromaa, Arpo; Kaprio, Jaakko

doi:10.1093/hmg/ddp322

Cited by 154 publications

(110 citation statements)

References 21 publications

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“…Thus, using cigarettes per day and self-reported nicotine dependence as measures for smokingrelated toxin and carcinogen exposure do not fully capture the health risks associated with smoking. This evidence builds on prior findings that showed a strong association between the CHRNA5-CHRNA3-CHRNB4 locus and another smoking biomarker, cotinine, a metabolite of nicotine (7,38,39). Each biomarker has its advantages.…”

Section: Original Researchsupporting

confidence: 69%

“…The variance in these two biomarkers, relative to cigarettes per day, explained by the key variant in CHRNA5-CHRNA3-CHRNB4 appears to be similar. We found rs16969968-rs1051730 explains 2.1% of the variance in CO compared with 0.5% of the variance in cigarettes per day, and a prior study in European smokers found this same locus explained 4.3% of the variance in cotinine versus 0.9% of the variance in cigarettes per day (38).…”

Section: Original Researchsupporting

confidence: 61%

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Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Bloom¹,

Hartz²,

Baker

et al. 2014

Annals ATS

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Rationale: The CHRNA5-CHRNA3-CHRNB4 locus is associated with self-reported smoking behavior and also harbors the strongest genetic associations with chronic obstructive pulmonary disease (COPD) and lung cancer. Because the associations with lung disease remain after adjustment for self-reported smoking behaviors, it has been asserted that CHRNA5-CHRNA3-CHRNB4 variants increase COPD and lung cancer susceptibility independently of their effects on smoking.Objectives: To compare the genetic associations of exhaled carbon monoxide (CO), a biomarker of current cigarette exposure, with self-reported smoking behaviors.Methods: A total of 1,521 European American and 247 African American current smokers recruited into smoking cessation studies were assessed for CO at intake before smoking cessation. DNA samples were genotyped using the Illumina Omni2.5 microarray. Genetic associations with CO and smoking behaviors (cigarettes smoked per day, Fagerstrom test for nicotine dependence) were studied. Measurements and Main Results:Variants in the CHRNA5-CHRNA3-CHRNB4 locus, including rs16969968, a nonsynonymous variant in CHRNA5, are genomewide association study-significantly associated with CO (b = 2.66; 95% confidence interval [CI], 1.74-3.58; P = 1.65 3 10 28 ), and this association remains strong after adjusting for smoking behavior (b = 2.18; 95% CI, 1.32-3.04; P = 7.47 3 10 27 ). The correlation between CO and cigarettes per day is statistically significantly lower (z = 3.43; P = 6.07 3 10 24 ) in African Americans (r = 0.14; 95% CI, 0.02-0.26; P = 0.003) than in European-Americans (r = 0.36; 95% CI, 0.31-0.40; P = 0.0001).Conclusions: Exhaled CO, a biomarker that is simple to measure, captures aspects of cigarette smoke exposure in current smokers beyond the number of cigarettes smoked per day. Behavioral measures of smoking are therefore insufficient indices of cigarette smoke exposure, suggesting that genetic associations with COPD or lung cancer that persist after adjusting for self-reported smoking behavior may still reflect genetic effects on smoking exposure.

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Section: Original Researchsupporting

confidence: 69%

Section: Original Researchsupporting

confidence: 61%

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Bloom¹,

Hartz²,

Baker

et al. 2014

Annals ATS

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“…Previously, investigators conducted a single locus analysis between serum cotinine levels and the cluster of nicotinic receptor subunit genes on chromosome 15 (Keskitalo et al, 2009). They showed larger effect sizes for serum cotinine in comparison to the cigarettes per day phenotype, and suggested that future studies concerning the effects of nicotine should strive to use cotinine levels from serum or saliva rather than self-reported smoking quantity as a measure of nicotine Gene-Centric analysis of serum cotinine levels A Hamidovic et al intake or its regulation.…”

Section: Discussionmentioning

confidence: 99%

“…As with previous genetic association analyses of cotinine levels Keskitalo et al, 2009), we evaluated association between serum cotinine levels and age, gender, BMI, and education. In the African American cohort, we found associations with BMI (p ¼ 0.025) and education (p ¼ 0.008), and in the European American cohort we found associations with age (p ¼ 0.003), gender (p ¼ 0.004), and education (p ¼ 0.023).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…It has a longer half-life than nicotine, and it is widely used as a biomarker for nicotine exposure. Serum cotinine levels provide a more accurate measure of nicotine intake than self-reported cigarettes per day and the preference of using serum cotinine in research over cigarettes per day has been suggested in both genetic (Keskitalo et al, 2009) and non-genetic (Gorber et al, 2009) literature.…”

Section: Introductionmentioning

confidence: 99%

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Gene-Centric Analysis of Serum Cotinine Levels in African and European American Populations

Hamidovic

Goodloe

Bergen

et al. 2011

Neuropsychopharmacol

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To date, most genetic association studies of tobacco use have been conducted in European American subjects using the phenotype of smoking quantity (cigarettes per day). However, smoking quantity is a very imprecise measure of exposure to tobacco smoke constituents. Analyses of alternate phenotypes and populations may improve our understanding of tobacco addiction genetics. Cotinine is the major metabolite of nicotine, and measuring serum cotinine levels in smokers provides a more objective measure of nicotine dose than smoking quantity. Previous genetic association studies of serum cotinine have focused on individual genes. We conducted a genetic association study of the biomarker in African American (N ¼ 365) and European American (N ¼ 315) subjects from the Coronary Artery Risk Development in Young Adults study using a chip containing densely-spaced tag SNPs in B2100 genes. We found that rs11187065, located in the non-coding region (intron 1) of insulin-degrading enzyme (IDE), was the most strongly associated SNP (p ¼ 8.91 Â 10 À6 ) in the African American cohort, whereas rs11763963, located on chromosome 7 outside of a gene transcript, was the most strongly associated SNP in European Americans (p ¼ 1.53 Â 10 À6 ). We then evaluated how the top variant association in each population performed in the other group. We found that the association of rs11187065 in IDE was also associated with the phenotype in European Americans (p ¼ 0.044). Our top SNP association in European Americans, rs11763963 was non-polymorphic in our African American sample. It has been previously shown that psychostimulant self-administration is reduced in animals with lower insulin because of interference with dopamine transmission in the brain reward centers. Our finding provides a platform for further investigation of this, or additional mechanisms, involving the relationship between insulin and self-administered nicotine dose.

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Genetic Epidemiology of Smoking Behaviour and Nicotine Dependence

Kaprio

2011

Encyclopedia of Life Sciences

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The public health significance of sustained smoking is overwhelming. The genetic epidemiology and architecture of smoking behaviour and nicotine dependence have been studied for several decades. Twin, family and adoption studies show consistent evidence for genetic effects on many aspects of smoking behaviour and nicotine dependence. Gene–environment interactions have been detected, such as parental monitoring moderating genetic vulnerability for smoking initiation. Molecular genetic analyses have only recently identified few genes consistently associated with amount smoked and nicotine dependence, whereas large genome‐wide association studies have identified only a handful of genes associated with nicotine dependence. The nicotinic receptor alpha 5 gene ( CHRNA5 ) variant associated with nicotine dependence in genetic association studies is functional. Further studies with more sophisticated phenotypes, larger sample sizes and better measures of the environment are needed. Key Concepts: Smoking behaviour and nicotine dependence aggregate in families. Genetic liability underlies this familial aggregation. The heritability of smoking behaviour is moderate, but varies between populations. The genetic architecture of nicotine dependence is poorly known. Large genome‐wide association studies have identified only a handful of genes associated with nicotine dependence. The nicotinic receptor alpha 5 gene variant associated with nicotine dependence in genetic association studies is functional. This functional variant affects nicotine intake in animal models. Gene–environment interactions have been detected for smoking behaviours, such as parental monitoring moderating genetic vulnerability in youth.

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Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15

Cited by 154 publications

References 21 publications

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Gene-Centric Analysis of Serum Cotinine Levels in African and European American Populations

Genetic Epidemiology of Smoking Behaviour and Nicotine Dependence

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