Haplotype-Based Association and In Silico Studies of OPRM1 Gene Variants with Susceptibility to Opioid Dependence Among Addicted Iranians Undergoing Methadone Treatment

摘要

The associations of OPRM1 gene variants with opioid dependence have been demonstrated. This study investigated the association of rs495491, rs1799971 (A118G), rs589046, and rs10457090 variants of OPRM1 gene with opium dependence and their haplotypes among addicted individuals undergoing methadone treatment. Moreover, we investigated whether any of these variants were associated with libido dysfunction or insomnia among addicted people. A total of 404 individuals were genotyped by amplification refractory mutation system (ARMS) PCR. In silico studies were designed through homology modeling of A118G structures (N40 and D40) and docked with 41 FDA-approved drugs of OPRM1 protein by SWISS-MODEL, COACH, MolProbity, ProSA, Errat, Glide XP, and Autodock 4. Results revealed that rs495491, A118G, rs589046, and rs10457090 were significantly associated with opium dependence under recessive (P = 6.66E-10), dominant (P = 0.017), co-dominant (P = 0.001), and recessive (P = 9.28E-6) models of inheritance, respectively. Further analyses indicated three significant haplotypes including A-A-A-C (P-permutation < 1E-9), G-G-A-C (P-permutation = 0.04), and G-A-G-C (P-permutation = 8.69E-4). Genotype-phenotype associations of OPRM1 variants with insomnia and libido dysfunction showed no significant association. Docking showed the higher binding affinity of N40 rather than D40 model; however, methadone and morphine were bonded with D40 structure more powerful. Consequently, rs495491, A118G, rs589046, and rs10457090 were associated with opioid dependence among Iranians; also, A118G might be the most remarkable marker of OPRM1 owing to its vital structural roles.