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.

BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.

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