Introduction: Dopamine systems in the CNS are decisively implicated in the motivational and rewarding properties of nicotine. The dopamine D2 receptor (DRD2) plays a pivotal role by promoting these properties, making this gene a good candidate for association studies. Several single nucleotide polymorphisms (SNPs) have been described to influence the expression of DRD2. The amount of expressed DRD2 will finally be the result of the sum and/or interaction of several functional polymorphisms located at the respective DNA strand forming a distinct haplotype. Thus, the knowledge about the distribution of the haplotypes in groups of subjects, differing by their smoking behaviour, would result in a better understanding of the putative associations compared to single SNP investigations.
Methods: 218 healthy subjects grouped for being never smokers, former smokers, and current smokers, were genotyped for the following polymorphisms: -141 ins(I)/del(D), STRPi2 (intron 2), C957T (exon 7), A1385G (exon 8), and TaqIA. Regular immoderate alcohol consumption was an exclusion criterion.
Results: In the total study group four haplotypes represented 90% of the haplotypes, with I-T-A-A2, I-C-G-A2, I-C-A-A1, and D-C-G-A2 accounting for around 50%, 20%, 10%, and 10%, respectively. I-C-G-A2 homozygosity was significantly higher in never smokers compared to ever smokers (current+former smokers) (chi2=36.585, df=1, p<0.001). There was a significant difference in the daily cigarette consumption of current smokers with respect to the haplogenotype (chi2=3211.9, df=18, p=0.003). Current smokers with a haplogenotype containing at least one I-T-A-A2 allele showed a significant smaller daily cigarette consumption (15.1+/-7.93) compared to subjects with a genotype not bearing this allele (20.1+/-6.79; T=-2.06, df=61, p=0.044).
Conclusion: We have demonstrated an association of the distinct haplogenotype I/I-C/C-G/G-A2/A2 of the DRD2 gene with a reduced risk to become a smoker in Caucasians of German origin. This protection may result from an association of this haplotype with a reduced activation of the dopaminergic neurotransmission by nicotine. Moreover, in current smokers, higher daily cigarette consumption is associated with those haplogenotypes that do not contain the I-T-A-A2 haplotype.