A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent
Tekijät: Buchwald Jadwiga, Chenoweth Meghan J., Palviainen Teemu, Zhu Gu, Benner Christian, Gordon Scott, Korhonen Tellervo, Ripatti Samuli, Madden Pamela A. F., Lehtimäki Terho, Raitakari Olli T., Salomaa Veikko, Rose Richard J., George Tony P., Lerman Caryn, Pirinen Matti, Martin Nicholas G., Kaprio Jaakko, Loukola Anu, Tyndale Rachel F.
Kustantaja: NATURE PUBLISHING GROUP
Julkaisuvuosi: 2021
Journal: Molecular Psychiatry
Tietokannassa oleva lehden nimi: MOLECULAR PSYCHIATRY
Lehden akronyymi: MOL PSYCHIATR
Vuosikerta: 26
Aloitussivu: 2212
Lopetussivu: 2223
Sivujen määrä: 12
ISSN: 1359-4184
eISSN: 1476-5578
DOI: https://doi.org/10.1038/s41380-020-0702-z
Rinnakkaistallenteen osoite: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483250/
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 similar to 38% of NMR variation, a substantial increase from the similar to 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.
