A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

• DOI: 10.1371/journal.pgen.1005498
• Publication Date: 2015-09-25T18:13:24Z
• Authors: Anu Loukola; Jadwiga Buchwald; Richa Gupta; Teemu Palviainen; Jenni Hällfors; Emmi Tikkanen; Tellervo Korhonen; Miina Ollikainen; Antti-Pekka Sarin; Samuli Ripatti; Terho Lehtimäki; Olli Raitakari; Veikko Salomaa; Richard J. Rose; Rachel F. Tyndale; Jaakko Kaprio
• Keywords: CYP2A6; Genome-wide Association Study; Cotinine; Genetic Association; SNP

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on rate metabolism. Our objective was to use metabolite ratio (NMR), an established biomarker rate, in genome-wide association study (GWAS) identify novel genetic variants influencing A heritability estimate 0.81 (95% CI 0.70–0.88) obtained NMR using monozygotic dizygotic twins FinnTwin cohort. We performed GWAS cotinine-verified current smokers three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by meta-analysis 1518 subjects, annotated significant SNPs methylation quantitative loci (meQTL) analyses. detected 19q13 719 exceeding significance within 4.2 Mb region. The strongest evidence emerged CYP2A6 (min p = 5.77E-86, intron 4), main metabolic enzyme nicotine. Other interesting genes signals included CYP2B6, CYP2A7, EGLN2, NUMBL. Conditional analyses revealed independent 19q13, all located or immediate vicinity CYP2A6. score constructed showed quantity (p 0.0019) two samples. meQTL results that values 16 CpG sites region are affected genotypes SNPs, according causal inference test, some effect mediated through methylation. To our knowledge, this first NMR. enclose 19q13.2. explain strikingly large fraction variance (up 31%) these we provide plausible epigenetic mechanisms