Epistatic effects between variants of kappa-opioid receptor gene and A118G of mu-opioid receptor gene increase susceptibility to addiction in Indian population

摘要

Objective: Unequivocal evidence suggests contribution of κ-opioid receptor (KOR) in addiction to drugs of abuse. A study was undertaken to identify the single nucleotide polymorphisms (SNP) at selective areas of kappa opioid receptor 1 (OPRK1) gene in heroin as well as in alcohol addicts and to compare them with that in control population. The potential interaction of the identified KOR SNPs with A118G of μ opioid receptor was also investigated. Methods: Two hundred control subjects, one hundred thirty heroin and one hundred ten alcohol addicts, all male and residing in Kolkata, a city in eastern India, volunteered for the study. Exons 3 and 4 of OPRK1 and the SNP, A118G of mu opioid receptor 1 (OPRM1) in the DNA samples were genotyped by sequencing and restriction fragment length polymorphism respectively. The SNPs identified in the population were analyzed by odds ratio and its corresponding 95% confidence interval was estimated using logistic regression models. SNP-SNP interactions were also investigated. Results: Three SNPs of OPRK1, rs16918875, rs702764 and rs963549, were identified in the population, none of which showed significant association with addiction. On the other hand, significant association was observed for A118G with heroin addiction (χ 2=7.268, P=0.0264) as well as with alcoholic addition (χ 2=6.626, P=0.0364). A potential SNP-SNP interaction showed that the odds of being addicted was 2.51 fold in heroin subjects [CI (95%)=1.1524 to 5.4947, P=0.0206] and 2.31 fold in alcoholics [CI (95%)=1.025 to 5.24, P=0.0433] with the OPRK1 (rs16918875) and A118G risk alleles than without either. A significant interaction was also identified between GG/AG of A118G and GG of rs702764 [O.R (95%)=2.04 (1.279 to 3.287), P=0.0029] in case of opioid population. Conclusion: Our study suggests that set associations of polymorphisms may be important in determining the risk profile for complex diseases such as addiction.