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Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci
Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci
Background DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N = 310). Results DNA methylation at 50 CpG sites was associated (FDR < 0.05) with cotinine levels, 17 of which are novel associations. As cotinine levels are influenced not only by nicotine intake but also by CYP2A6-mediated nicotine metabolism rate, we performed secondary analyses adjusting for genetic risk score of nicotine metabolism rate and identified five additional novel associations. We further assessed the potential role of genetic variants in the detected association between methylation and cotinine levels observing 124 cis and 3898 trans methylation quantitative trait loci (meQTLs). Nineteen of these SNPs were also associated with cotinine levels (FDR < 0.05). Further, at seven CpG sites, we observed a trend (P < 0.05) that altered DNA methylation mediates the effect of SNPs on nicotine exposure rather than a direct consequence of smoking. Finally, we performed replication of our findings in two independent cohorts of biochemically verified smokers (N = 450 and N = 79). Conclusions Using cotinine, a biomarker of nicotine exposure, we replicated and extended identification of novel epigenetic associations in smoking-related genes. We also demonstrated that DNA methylation in some of the identified loci is driven by the underlying genotype and may mediate the causal effect of genotype on cotinine levels. Electronic supplementary material The online version of this article (10.1186/s13148-018-0606-9) contains supplementary material, which is available to authorized users.
- University of Toronto Canada
- Institute for Molecular Medicine Finland Finland
- Vrije Universiteit Amsterdam Netherlands
- University of Helsinki Finland
- Institute for Molecular Medicine Finland, University of Helsinki Finland
Library of Congress Subject Headings: lcsh:Medicine lcsh:R lcsh:Genetics lcsh:QH426-470
Microsoft Academic Graph classification: Epigenetics Biology Single-nucleotide polymorphism DNA methylation CpG site Genotype Internal medicine medicine.medical_specialty medicine Endocrinology Methylation Cotinine chemistry.chemical_compound chemistry Nicotine medicine.drug
Epigenome-wide association study, Smoking, Cotinine, Genetic risk score, Nicotine metabolism, meQTL, Causal inference, Molecular mediation, NICOTINE METABOLITE RATIO, DIFFERENTIAL DNA METHYLATION, SELF-REPORTED SMOKING, CIGARETTE SMOKERS, BLOOD, BIOMARKER, PATHWAY, LUNG, CESSATION, ACCURACY, 3122 Cancers, 3111 Biomedicine, Adult, Aged, CpG Islands, Cytochrome P-450 CYP2A6, DNA Methylation, Epigenomics, Female, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Research, Genetics (clinical), Developmental Biology, Genetics, Molecular Biology, Causal inference, Cotinine, Epigenome-wide association study, Genetic risk score, meQTL, Molecular mediation, Nicotine metabolism, Smoking, /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_, Netherlands Twin Register (NTR), /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, SDG 3 - Good Health and Well-being, Netherlands Twin Register (NTR), SDG 3 - Good Health and Well-being
Epigenome-wide association study, Smoking, Cotinine, Genetic risk score, Nicotine metabolism, meQTL, Causal inference, Molecular mediation, NICOTINE METABOLITE RATIO, DIFFERENTIAL DNA METHYLATION, SELF-REPORTED SMOKING, CIGARETTE SMOKERS, BLOOD, BIOMARKER, PATHWAY, LUNG, CESSATION, ACCURACY, 3122 Cancers, 3111 Biomedicine, Adult, Aged, CpG Islands, Cytochrome P-450 CYP2A6, DNA Methylation, Epigenomics, Female, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Research, Genetics (clinical), Developmental Biology, Genetics, Molecular Biology, Causal inference, Cotinine, Epigenome-wide association study, Genetic risk score, meQTL, Molecular mediation, Nicotine metabolism, Smoking, /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_, Netherlands Twin Register (NTR), /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, SDG 3 - Good Health and Well-being, Netherlands Twin Register (NTR), SDG 3 - Good Health and Well-being
Library of Congress Subject Headings: lcsh:Medicine lcsh:R lcsh:Genetics lcsh:QH426-470
Microsoft Academic Graph classification: Epigenetics Biology Single-nucleotide polymorphism DNA methylation CpG site Genotype Internal medicine medicine.medical_specialty medicine Endocrinology Methylation Cotinine chemistry.chemical_compound chemistry Nicotine medicine.drug
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4. Guida F, Sandanger TM, Castagne R, Campanella G, Polidoro S, Palli D, et al. Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation. Hum Mol Genet. 2015;24(8):2349-59.
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7. Zeilinger S, Kuhnel B, Klopp N, Baurecht H, Kleinschmidt A, Gieger C, et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One. 2013;8(5):e63812. [OpenAIRE]
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9. Sayols-Baixeras S, Lluis-Ganella C, Subirana I, Salas LA, Vilahur N, Corella D, et al. Identification of a new locus and validation of previously reported loci showing differential methylation associated with smoking. The REGICOR study. Epigenetics. 2015;10(12):1156-65.
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- Academy of Finland (AKA)
- 265240
- Canadian Institutes of Health Research (CIHR)
- University of Toronto Canada
- Institute for Molecular Medicine Finland Finland
- Vrije Universiteit Amsterdam Netherlands
- University of Helsinki Finland
- Institute for Molecular Medicine Finland, University of Helsinki Finland
- Institute for Molecular Medicine Finland Finland
Background DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N = 310). Results DNA methylation at 50 CpG sites was associated (FDR < 0.05) with cotinine levels, 17 of which are novel associations. As cotinine levels are influenced not only by nicotine intake but also by CYP2A6-mediated nicotine metabolism rate, we performed secondary analyses adjusting for genetic risk score of nicotine metabolism rate and identified five additional novel associations. We further assessed the potential role of genetic variants in the detected association between methylation and cotinine levels observing 124 cis and 3898 trans methylation quantitative trait loci (meQTLs). Nineteen of these SNPs were also associated with cotinine levels (FDR < 0.05). Further, at seven CpG sites, we observed a trend (P < 0.05) that altered DNA methylation mediates the effect of SNPs on nicotine exposure rather than a direct consequence of smoking. Finally, we performed replication of our findings in two independent cohorts of biochemically verified smokers (N = 450 and N = 79). Conclusions Using cotinine, a biomarker of nicotine exposure, we replicated and extended identification of novel epigenetic associations in smoking-related genes. We also demonstrated that DNA methylation in some of the identified loci is driven by the underlying genotype and may mediate the causal effect of genotype on cotinine levels. Electronic supplementary material The online version of this article (10.1186/s13148-018-0606-9) contains supplementary material, which is available to authorized users.