Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
03
05
2019
accepted:
21
02
2020
revised:
18
02
2020
pmc-release:
10
09
2021
pubmed:
12
3
2020
medline:
12
10
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3'hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained ~38% of NMR variation, a substantial increase from the ~20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3'hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.
Identifiants
pubmed: 32157176
doi: 10.1038/s41380-020-0702-z
pii: 10.1038/s41380-020-0702-z
pmc: PMC7483250
mid: NIHMS1565522
doi:
Substances chimiques
Nicotine
6M3C89ZY6R
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2212-2223Subventions
Organisme : NCI NIH HHS
ID : R35 CA197461
Pays : United States
Organisme : NIAAA NIH HHS
ID : K02 AA018755
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : U01 DA020830
Pays : United States
Organisme : CIHR
ID : FDN-154294
Pays : Canada
Organisme : CIHR
ID : PJY-159710
Pays : Canada
Informations de copyright
© 2020. The Author(s), under exclusive licence to Springer Nature Limited.
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