Our results also indicated a significant sex-by-COMT interaction for withdrawal severity. Women with the Val/Val genotype reported greater difficulty concentrating and irritability than men who were with Val/Val or Met carriers. These findings are consistent with the sexually dimorphic activity of the COMT enzyme that may be mediated by multiple mechanisms including the estrogen response element in COMT promoter, reduced COMT mRNA expression by estradiol as well as breakdown of catechol estrogens by the COMT enzyme (63). Similar to our findings, other studies have shown that the Val/Val genotype may have greater influence in women for endophenotypes related to negative affect (53, 64). The association of greater irritability, and difficulty concentrating with the Val/Val genotype in women may contribute to greater difficulty of women quitting smoking than men. As mentioned before, the Val/Val genotype may be a risk factor for developing nicotine addiction (9) and poor treatment response to smoking cessation treatments (11–13). Whether COMT variation contributes to the greater difficulty of women to quit smoking remain to be examined.
