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Abstract
Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (−48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A −1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).
Highlights
Cigarette smoking is the single most preventable cause of lung cancer and a main source of morbimortality worldwide [1]
Our results suggest that genetic variants that can influence nicotine metabolization are those showing the strongest association with smoking status and smoking-related phenotypes
No significant association was observed for those genetic polymorphisms that are involved in the brain effects of nicotine through nicotinic acetylcholine (CHRNA3, CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1) and serotonin transporters (5HTT)
Summary
Cigarette smoking is the single most preventable cause of lung cancer and a main source of morbimortality worldwide [1]. More controversy exists on the specific genetic variants that have a functional significance on such phenotypes, with a strong rationale existing for polymorphisms in genes encoding nicotine-metabolizing enzymes in the liver [cytochrome P450 2A6 (CYP2A6) and B6 (CYP2B6)] and lungs (CYP2A13) [18]. Other candidate polymorphisms are in genes encoding neuronal nicotinic acetylcholine receptors (CHRNA3 and CHRN5), or in genes involved in dopaminergic, serotoninergic, cannabinoid and opioid pathways related to nicotine reward and dependence, such as dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1 dopamine D2), serotoninergic transporter [5-HTT, termed solute carrier family 6, member 4 (SLC6A4)] and receptor (HTR2A), cannabinoid receptor 1 (CNR1) and mu opioid receptor (OPRM1) [18]
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