Principal Investigator: Professor Rachel Tyndale
Department: University of TorontoTags: 55371, CYP2A6, genetics/genotyping, Mendelian randomisation, nicotine metabolite ratio/NMR, PheWAS, risk prediction
Cigarette smoking remains a leading preventable cause of illness and death. Currently, over a billion people worldwide smoke cigarettes. Our research aims to identify people at increased risk of developing smoking-related health problems. The main addictive component in cigarettes is nicotine. Nicotine is broken down in the body mostly by a protein molecule called CYP2A6. Genetic differences in CYP2A6 may indirectly elevate the risk for tobacco-related diseases such as lung cancer by changing the activity of CYP2A6, thereby influencing the rate of nicotine metabolism and smoking behaviours. Variation in CYP2A6 activity may also impact disease risk directly due to its involvement in the activation of harmful compounds present in tobacco. Our group has developed a test (CYP2A6 risk score) that predicts differences in nicotine metabolism among cigarette smokers based on individual genetic differences (variants) in the CYP2A6 gene. The CYP2A6 risk score captures about 30% of the variability in nicotine metabolism. Furthermore, the CYP2A6 risk score predicts the chances that someone will successfully quit smoking on available treatments. The CYP2A6 risk score as a genetic marker has an advantage of reflecting CYP2A6 activity in all populations, whereas non-genetic markers of nicotine metabolism can be only measured in regular smokers.
We observed an association between one of the variants included in the CYP2A6 risk score with chronic lower respiratory diseases and body mass index in publicly available platforms based on the UK-Biobank data. Therefore, we propose using the UK-Biobank genome- and phenome-wide data to 1) identify disease traits potentially linked to the CYP2A6 risk score and, and 2) use additional advanced statistical techniques to look for evidence supporting causal relationships between CYP2A6 and those traits.
This research will provide a better understanding of traits that may be connected to nicotine metabolism in smokers and non-smokers and will help identify individuals at risk of smoking-related health problems.