Our candidate gene analysis suggest possible association with the OPRM1 A118G non-synonymous (N40D) SNP rs1799971 and the nicotine withdrawal sensitivity score (P = 0.07, Q = 0.08). This SNP has been associated with functional differences in physiological (49) or therapeutic (50–51) responses to opioids in vivo and in vitro (52), although there are negative studies (53–54). In addition to increased affinity for endorphin, an endogenous MOR ligand, and increased post-synaptic potassium current (52), differential allelic expression of the gene has been another mechanism hypothesized to account for potential functional differences between alleles (55). A meta analysis of rs1799971 allelic association utilizing 28 samples of individuals fulfilling DSM-III, DSM-IV or ICD-10 critieria for alcohol, opioid, methamphetamine or mixed substance dependence reported no association (56). Because no exclusions for smoking behaviors were made in case or control samples, this particular meta analysis may not be informative for substance dependence that involves nicotine dependence alone or in combination with other substance dependence. rs1799971 is not significantly associated with nicotine dependence in some population based (20, 57) or treatment seeking smoker (28) samples. With
