Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6.
- Authors
- Bloom, A Joseph; Harari, Oscar; Martinez, Maribel; Madden, Pamela A F; Martin, Nicholas G; Montgomery, Grant W; Rice, John P; Murphy, Sharon E; Bierut, Laura J; Goate, Alison
- Year
- 2012
- Journal
- Human molecular genetics
- PMID
- 22451501
- DOI
- 10.1093/hmg/dds114
- PMCID
- PMC3373237
This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here, we apply this model to assess associations between genotype, inferred nicotine metabolism and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence, demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations.
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study. | Giratallah H et al. | — | 2024 | → |
| Inhibition of Nicotine Metabolism by Cannabidiol (CBD) and 7-Hydroxycannabidiol (7-OH-CBD). | Nasrin S et al. | — | 2023 | → |
| Nicotine Metabolism Predicted by CYP2A6 Genotypes in Relation to Smoking Cessation: A Systematic Review. | Jones SK et al. | — | 2022 | → |
| Biochemistry of nicotine metabolism and its relevance to lung cancer. | Murphy SE | — | 2021 | → |
| Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity. | El-Boraie A et al. | — | 2020 | → |
| Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes. | Bloom AJ et al. | — | 2019 | → |
| Prevalence of Some Genetic Risk Factors for Nicotine Dependence in Ukraine. | Bashynska V et al. | — | 2019 | → |
| Strain-specific altered nicotine metabolism in 3,3'-diindolylmethane (DIM) exposed mice. | Bloom AJ et al. | — | 2019 | → |
| CYP2A6 metabolism in the development of smoking behaviors in young adults. | Olfson E et al. | — | 2018 | → |
| From genes to treatments: a systematic review of the pharmacogenetics in smoking cessation. | Salloum NC et al. | — | 2018 | → |
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| Pathways to precision medicine in smoking cessation treatments. | Chen LS et al. | — | 2018 | → |
| The Value of Biosamples in Smoking Cessation Trials: A Review of Genetic, Metabolomic, and Epigenetic Findings. | Saccone NL et al. | — | 2018 | → |
| Use of polygenic risk scores of nicotine metabolism in predicting smoking behaviors. | Chen LS et al. | — | 2018 | → |
| A Novel Tobacco Use Phenotype Suggests the 15q25 and 19q13 Loci May be Differentially Associated With Cigarettes per Day and Tobacco-Related Problems. | Richmond-Rakerd LS et al. | — | 2017 | → |
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| Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. | Murphy SE et al. | — | 2014 | → |
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| Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). | Chen LS et al. | — | 2014 | → |
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| The Genetics, Neurogenetics and Pharmacogenetics of Addiction. | Demers CH et al. | — | 2014 | → |
| Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. | Bloom AJ et al. | — | 2014 | → |
| A compensatory effect upon splicing results in normal function of the CYP2A6*14 allele. | Bloom AJ et al. | — | 2013 | → |
| CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes. | Bloom AJ et al. | — | 2013 | → |
| Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption. | Bloom AJ et al. | — | 2013 | → |