A meta-analytic review of the CYP2A6 genotype and smoking behavior

Individuals who carry variant alleles of the CYP2A6 gene are poor metabolizers of nicotine and are believed to be more sensitive to nicotine's aversive effects than those with normal alleles. This sensitivity is hypothesized to exert a protective effect against smoking initiation and lead to lower cigarette consumption among smokers with variant alleles. Although early studies found an association between variant CYP2A6 alleles and smoking behavior, more recent studies have not. A meta-analysis was conducted to help resolve these conflicting results. A literature search produced 11 studies providing information on CYP2A6 genotyping in smokers or nonsmoking control subjects. Participants were classified as smokers (ever-smokers or current smokers) or nonsmokers (former or never-smokers), and as carrying normal CYP2A6 genes or one or more variant alleles. Information regarding cigarette consumption also was included. Effect sizes were calculated from each study and then aggregated into an overall effect size. This analysis failed to find any empirical evidence of a relationship between variant CYP2A6 alleles and smoking status (n=4,091) or cigarette consumption (n=1,537). Although these results suggest the CYP2A6 gene is not associated with smoking behavior, the use of broad smoking status classifications (e.g., ever- vs. never-smoking), which fail to account for the complex nature of gene expression (e.g., gene-gene interactions), may have obscured the relatively modest genetic influences that might have been present. What role, if any, the CYP2A6 gene plays in smoking behavior will be understood only if future research addresses these methodological concerns.