ASSOCIATION BETWEEN PROOPIOMELANOCORTIN GENE VARIATION AND ALCOHOL DEPENDENCE IN JAPANESE

Abstract Background & Objectives The contribution of genetic factors in alcohol dependence is approximately 0.4- 0.6, indicating that genetic variations can be markers for individual vulnerability to alcohol dependence. Racial and ethnic differences in genetic backgrounds lead to different effect sizes of each genetic variation in the analyses and would be expected to affect the results of association studies. The endogenous opioid system has been reportedly implicated in addiction including alcohol dependence. In the present study, we focused on the Proopiomeranocortin (POMC) gene which encodes an endogenous opioid, β-Endorphin and examined the effects of genetic variations on alcohol dependence in Japanese. Method This study included 425 Japanese patients diagnosed with alcohol abuse/dependence by DSM-III- R and 339 control subjects matched to alcoholic patients on gender and age. The statistical significance of associations between genetic variations in alcohol-dependent patients and control subjects was evaluated with non-parametric analyses. Linkage disequilibrium (LD) was examined with the SNVs identified by direct sequencing around the POMC gene. Result The POMC C-1802T variation was significantly different between patients with alcohol dependence and control subjects. The significant difference in the recessive model was confirmed after correction by ALDH2 rs672 variation. Three LD blocks were constructed around the POMC gene, but no one including the variation was identified in Japanese. Discussion & Conclusion A genetic variation in 5 flanking region of the POMC gene appears to be associated with alcohol dependence in Japanese. This genetic variation may alter the expression of the POMC gene and affect vulnerability to alcohol dependence. Nalmefene, an inverse agonist of the μ-opioid receptor and a partial agonist of the κ-opioid receptor, is used in the treatment of alcohol dependence in Japan. The frequency of this genetic variation varies widely among racial groups around the world and is expected to influence the efficacy of alcoholism medications such as naltrexone and nalmefene.