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

Abstract

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

Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis

“…Importantly, loci in the 19q13 region were previously implicated in quantity smoked by the TAG Consortium in their combined analysis and also by the ENGAGE 11 analysis and, recently, by Loukola et al 41 ; the region has been proposed as a plausible candidate for further investigation in relation to smoking quantity given its role in nicotine metabolism (see e.g., 13 ). We now add age at initiation to the list of smoking phenotypes to be further investigated in relation to this biologically plausible region.…”

Pharmacogenetic Optimization of Smoking Cessation Treatment

“…Smokers with faster rates of nicotine metabolism, as determined by the NMR, have higher quit rates on varenicline versus the nicotine patch; in contrast, varenicline is not superior to the patch in slower metabolizers [22] (Figure 2). NMR genome-wide association studies have identified novel sources of genetic variation in CYP2A6 activity which may improve the optimization of treatment using CYP2A6 genomics and phenotype (NMR) in the future [78]. Future studies should aim to determine a) the optimal NMR cut-point for distinguishing between faster and slower metabolizers (see Outstanding Questions), and b) whether the utility of NMR, as opposed to using a purely genetics-based approach, may be limited by transient environmental influences.…”

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk

“…A recently published GWAS found 3 variants (rs56113850, rs113288603, and esv2663194) to be globally associated with nicotine metabolism (49). Of these, in our study, only rs56113850 was strongly associated with both CYP2A6 activity levels and lung cancer risk, while rs113288603 and esv2663194 ( CYP2A6 *12 ) were also associated with CYP2A6 activity, but were not strongly associated with lung cancer.…”