Why do young women smoke? VII COMT as a risk modifying gene for Nicotine dependence - role of gene-gene interaction, personality, and environmental factors.

Objectives: Catechol-O-methyltransferase (COMT) may be a risk modifying gene for Nicotine dependence (ND) rather than a direct susceptibility gene for this phenotype. Brain nicotinic cholinergic receptors modulate dopaminergic transmission, and several variants within the neighboring CHRNA5-CHRNA3 genes have been associated with ND. Therefore, it is biologically reasonable to study the interactive contribution of COMT and the CHRNA5 and CHRNA3 genes to ND.

Methods: Using a case-control sample of 90 young, Israeli, Jewish female smokers (FTND ≥ 4) and 108 controls (FTND = 0 during heaviest period of smoking), we studied association with ND of 8 COMT tagging SNPs, their interaction with tagging CHRNA5-A3 SNPs and the role of background, personality, and environmental factors.

Results: None of the COMT SNPs were associated directly with ND. In pairwise interaction analysis of SNPs from the two loci (COMT SNP-CHRNA5-CHRNA3 SNP), the interaction of intronic COMT SNP, rs9332377, with CHRNA3 3'UTR SNP rs660652 was significantly associated with ND (p = 0.0005), withstanding correction for multiple testing.

Conclusion: Addition of the genetic interaction variable into a model of non-genetic ND predictors [parental smoking, novelty seeking (NS), and lifetime history of trauma], substantially increases the percentage of ND variance explained by the model, as well as the percentage of cases correctly identified by it.