Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the <i>DRD2</i> TaqIA (rs1800497) and rs6277" genes_norm="1813">C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence.
Considering new evidence supporting the association of DRD2 and its adjacent gene ankyrin repeat and kinase domain containing 1 (ANKK1) with various addictions, in this paper, we provide an updated view of the involvement of variants in DRD2 and ANKK1 in the etiology of nicotine dependence (ND) and alcohol dependence (AD) based on linkage, association, and molecular studies.
NCAM1-TTC12-ANKK1-DRD2 region variation was significantly associated with the Automaticity subscale and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and ND.
Among smokers with DRD2rs1079597 GG//MAOA rs309850 3-repeat, the OR of heavier smoking was 2.67 times higher (95% confidence interval [CI]: [1.08, 6.59], p = .031) and the score on the Fagerstrom test for nicotine dependence was higher (4.26 vs. 2.83) than in those with DRD2rs1079597 AA//MAOA rs309850 3-repeat.
NCAM1-TTC12-ANKK1-DRD2 region loci and haplotypes were significantly associated with the motive of Automaticity and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and nicotine dependence.
This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population.
Our findings suggest that the DRD2C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.
We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9.
To investigate further the relationships between the DRD2 genotypes, cigarette use and nicotine dependence, we examined the prevalence of polymorphisms in the TaqIA (A1 and A2) and the TaqIB (B1 and B2) alleles among a series of 608 non-Hispanic White bladder cancer patients and 608 matched controls.
This study confirms the reported association of the CHRNA3 locus with nicotine dependence and shows the involvement of two independent DRD2 polymorphisms in nicotine dependence.
Several SNPs (rs7131056, rs4274224, rs4648318, and rs6278) in DRD2, along with the Taq IA polymorphism (rs1800497) in ANKK1, revealed initial significant associations with ND in European Americans, but not after correction for multiple testing, indicating a weak association of DRD2 with ND.
Once smoking started, carriers of the T allele of a single nucleotide polymorphism of DRD2 (rs4648317) reported higher rates of current smoking and scored higher on nicotine dependence than their allelic counterparts.
There was relatively weak evidence for association of the flanking DRD2 and NCAM1 markers to ND, but very strong evidence of association of multiple SNPs at TTC12 and ANKK1 in both populations (minimal P=0.0007 in AAs and minimal P=0.00009 in EAs), and in the pooled sample, as well as strong evidence for highly significant association of a single haplotype spanning TTC12 and ANKK1 to ND in the pooled sample (P=0.0000001).
We investigated the association between smoking behavior and genetic variations in the D2 dopamine receptor (DRD2), which mediates nicotine dependence.
The initial pharmacogenetic studies of pharmacotherapies approved by the United States Food and Drug Administration for treatment of nicotine dependence-nicotine replacement (nicotine gum, nicotine nasal spray, and transdermal nicotine) and bupropion-have identified candidate alleles at the dopamine D2 receptor gene and mu opioid receptor gene that may predict therapeutic response.
Bupropion is a weak dopamine reuptake inhibitor, and individual genetic variation in the dopamine D2 receptor has been associated with nicotine dependence in case-control studies.