Gene-gene interaction of μ-opioid receptor and GluR5 kainate receptor subunit is associated with smoking behavior in a Greek population: presence of a dose allele effect.

Abstract

Components of nicotine reward system can potentially influence smoking behavior. The μ-opioid receptor (OPRM1) binds the endogenous opioid peptide β-endorphin and mediates the reinforcing effects of nicotine, while the GluR5 kainate receptor subunit (encoded by GRIK1 gene), a binding site for known mediators of glutamate neurotransmission, potentially affects the glutaminergic system that is also indirectly implicated in the reward system. In the present study, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms and their interactions were analyzed in 132 smoking initiators (SI) and 144 non-initiators (NI) of Greek origin, using the PCR-RFLP method. No differences were found in the genotype or allele distribution of OPRM1 A118G and GRIK1 rs2832407C>A between SI and NI. However, we found a significant interaction of OPRM1 A118G and GRIK1 rs2832407C>A genotypes associated with smoking initiation in a model adjusted for age, sex, BMI and type 2 diabetes mellitus (odds ratio=1.341, 95% CI 1.024-1.755, p=0.033). A dose effect of OPRM1 and GRIK1 variant alleles was present. Increased number of variant alleles (from 0 to 4) was associated with smoking initiation in the same adjusted model (odds ratio=1.537, 95% CI 1.030-2.293, p=0.036). Smoking phenotype is a complex interaction of genetic and environmental factors. In the present study, we have shown that gene-gene interaction of components of different systems associated with nicotine reinforcing effects, such as OPRM1 and GRIK1, rather than one gene polymorphism, is associated with smoking behavior.