The non-synonymous SNP rs1042114 (80G>T, Phe27Cys) changes the evolutionary conserved phenylalanine to cysteine in the extracellular N terminus. Interestingly, the reference 80G-allele is the minor allele and is absent in Asians, rare in Africans, and has a minor allele frequency (MAF) of 0.1, in Europeans. One of the possible explanations for this phenomenon may be selective advantage for the 80T-allele, but the biological mechanism underlying this potential advantage has yet to be identified. The minor 80G-allele has been found to be associated with OD in EA subjects (Zhang et al. 2008). These results were not found in a family-based association study of 18 SNPs with AD (219 EA families), a case control association study with “illicit drug dependence”, and in a small subsample with OD (Xuei et al. 2007). This SNP was not included in the array used in our studies of heroin addiction (Levran et al. 2008; Levran et al. 2009). Functional studies revealed that the two variants (27Phe and 27Cys) have identical pharmacological properties, but differ in maturation efficiency, stability at the plasma membrane, and Ca2+ signaling regulation (Leskela et al. 2009; Tuusa and Petaja-Repo 2011).
