CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3'-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10-6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10-5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10-4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource.

Genetic variation in fatty acid amide hydrolase (FAAH): Associations with early drinking and smoking behaviors.

BACKGROUND: The endocannabinoid system is implicated in psychiatric disorders and drug dependence. Within this system, fatty acid amide hydrolase (FAAH) metabolizes endocannabinoids. Individuals with A-group genotypes (C/A or A/A) of a common FAAH variant (rs324420; C > A; Pro129Thr) have slower enzymatic activity compared to C-group individuals (C/C genotype). Slow FAAH activity is differentially associated with alcohol and nicotine use. METHODS: Among European-ancestry participants in the NDIT study (n = 249-607), genotype associations with past-year binge drinking in young adults were estimated in logistic regression models. In adolescents, hazard ratios (HR) were estimated from Cox proportional hazards models to assess the FAAH genotype group association with time to drinking initiation and attaining drinking frequency outcomes. HR were also used to assess genotype effect on time to smoking initiation and attaining early smoking milestones (e.g., first inhalation, ICD-10 dependence). RESULTS: Compared to those in the C-group, those in the A-group had higher odds of binge drinking at ages 20 (Odds ratio (OR) = 2.16, 95 % CI 1.36-3.42) and 30 (OR = 1.61, 95 % CI 1.10-2.36). Time to initiation of drinking and daily drinking was faster in adolescents in the A-group (HR = 1.39, 95 % CI 1.09-1.77 and HR = 2.24, 95 % CI 1.05-4.76, respectively). Time to smoking initiation was faster in the A-group (HR = 1.20, 95 % CI 1.04-1.39); however, time to smoking milestones among adolescent smokers was not consistently different for the A- versus C-groups (HR = 0.43 to 1.13). CONCLUSIONS: Slow FAAH activity (A-group) was associated with greater risks for binge drinking, drinking initiation and escalation, and cigarette smoking initiation, but had little impact on the escalation in cigarette smoking behaviors.

Does genetic variation in a bitter taste receptor gene alter early smoking behaviours in adolescents and young adults?

BACKGROUND AND AIMS: Variation in the TAS2R38 taste receptor gene alters the ability to taste bitter compounds. We tested whether TAS2R38 variation influences early smoking behaviours in adolescence, a critical period of acquisition when taste may influence the natural course of tobacco use. DESIGN AND PARTICIPANTS: Observational study (Nicotine Dependence in Teens [NDIT]). Cox proportional hazards models were conducted using data from European ancestry adolescent participants who initiated smoking during follow-up (n = 219, i.e. incident smokers). In young adulthood, cross-sectional analyses were restricted to European ancestry self-reported current smokers at age 24 (n = 148). SETTING: Montréal, Canada. MEASUREMENTS: In adolescents, the rates of attaining early smoking milestones were estimated for tasters {PAV diplotypes (i.e. PAV/PAV or PAV/AVI)} versus non-tasters {AVI diplotype (i.e. AVI/AVI)}. In young adults, associations between tasting status and a nicotine intake biomarker (cotinine + 3'hydroxycotinine) and past-week cigarette consumption were assessed. FINDINGS: Among incident smokers, similar rates to first whole cigarette were found between the diplotype groups (hazard ratio [HR], 1.05; 95% confidence interval (CI), 0.75-1.48; P = 0.765). However, smokers with the PAV (vs AVI) diplotypes attained monthly smoking more rapidly (HR, 1.55; 95% CI, 1.04-2.32; P = 0.033) and had faster conversion to three different measures of tobacco dependence (International Classification of Diseases: HR, 2.29; 95% CI, 0.99-5.28; P = 0.052; modified Fagerström Tolerance Questionnaire: HR, 3.02, 95% CI, 1.04-8.79; P = 0.043; Hooked on Nicotine Checklist: HR, 1.87; 95% CI, 0.98-3.60; P = 0.059). At age 24, those with PAV (vs AVI) diplotypes had higher mean cotinine + 3'hydroxycotinine (197 vs 143 ng/mL; P = 0.053). CONCLUSIONS: Adolescents with a genetic variation increasing their ability to taste bitter compounds appear to escalate more quickly to monthly smoking and tobacco dependence during adolescence and have higher nicotine intake in young adulthood versus those without that genetic variation.

Functional nucleic acids as in vivo metabolite and ion biosensors.

Characterizing the role of metabolites, metals, and proteins is required to understand normal cell function, and ultimately, elucidate the mechanism of disease. Metabolite concentration and transformation results collected from cell lysates or fixed-cells conceal important dynamic information and differences between individual cells that often have profound functional consequences. Functional nucleic acid-based biosensors are emerging tools that are capable of monitoring ions and metabolites in cell populations or whole animals. Functional nucleic acids (FNAs) are a class of biomolecules that can exhibit either ligand binding or enzymatic activity. Unlike their protein analogues or the use of instrument-based analysis, FNA-based biosensors are capable of entering cells without disruption to the cellular environment and can report on the concentration, dynamics, and spatial localization of molecules in cells. Here, we review the types of FNAs that have been used as in vivo biosensors, and how FNAs can be coupled to transduction systems and delivered inside cells. We also provide examples from the literature that demonstrate their impact in practical applications. Finally, we comment on the critical limitations that need to be addressed to enable their use for single-cell dynamic tracking of metabolites and ions in vivo.