| Title |
Genome‐wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences
|
|---|---|
| Published in |
Addiction, November 2017
|
| DOI | 10.1111/add.14032 |
| Pubmed ID | |
| Authors |
Meghan J. Chenoweth, Jennifer J. Ware, Andy Z. X. Zhu, Christopher B. Cole, Lisa Sanderson Cox, Nikki Nollen, Jasjit S. Ahluwalia, Neal L. Benowitz, Robert A. Schnoll, Larry W. Hawk, Paul M. Cinciripini, Tony P. George, Caryn Lerman, Joanne Knight, Rachel F. Tyndale, on behalf of the PGRN‐PNAT Research Group |
| Abstract |
The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus Whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. Genome-wide association study (GWAS). Multiple sites within Canada and the United States. AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n=504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n=450). Genome-wide SNP genotyping, the NMR (phenotype), and population substructure and NMR covariates. Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190, and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P=1.47e-39; beta=0.59 per C (versus T) allele, SE=0.045), located ~9.5kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in European descent individuals. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n=480). None of the hits were in UGT or OCT2 genes. Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African-American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours, and tobacco-related disease risk. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 2 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 55 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 55 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 10 | 18% |
| Student > Ph. D. Student | 8 | 15% |
| Researcher | 5 | 9% |
| Student > Doctoral Student | 4 | 7% |
| Professor | 3 | 5% |
| Other | 12 | 22% |
| Unknown | 13 | 24% |
| Readers by discipline | Count | As % |
|---|---|---|
| Psychology | 6 | 11% |
| Biochemistry, Genetics and Molecular Biology | 6 | 11% |
| Nursing and Health Professions | 6 | 11% |
| Medicine and Dentistry | 5 | 9% |
| Agricultural and Biological Sciences | 4 | 7% |
| Other | 9 | 16% |
| Unknown | 19 | 35% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 November 2017.
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#15,462,794
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Outputs from Addiction
#5,289
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#188,511
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Outputs of similar age from Addiction
#64
of 72 outputs
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