Effects of the Dopamine Receptor 2 (DRD2) and Its Genetic Variants on Smoking and Nicotine Dependence in African Americans

Nicotine dependence is highly heritable and influenced by increased expression of the dopamine receptor D2 (DRD2) gene and the Taq1A single nucleotide polymorphism (SNP). Previous research has demonstrated that, African-American smokers are more likely to be nicotine dependent and notably, the A1 allele of the Taq1A SNP is more prevalent in this population. Moreover, both DRD2 synonymous and non-synonymous SNPs have been found to affect the expression of the DRD2 gene. Therefore, SNPs were selected based on a modified version of the mapping by admixture linkage disequilibrium (MALD) algorithm, a theoretically powerful approach to mapping genetic variants that are involved in human disease. Using this approach, four SNPs that are more prevalent in populations of African descent were identified. These SNPs are found in functional regions of the gene, such as the 3' untranslated region (UTR) which may influence mRNA stability and gene expression.;Restriction fragment length polymorphism (RFLP) and pyrosequencing were used as methods to genotype DRD2 SNPs: rs6274, rs6276, and rs6279, as well as Taq1A (rs1800497) in a cohort of 473 African-American former and current smokers from Baltimore, MD (n = 378) and Washington, DC (n = 95). Clinical nicotine dependence was examined and measured in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), an independent and cumulative association of 3 or more clinical symptoms of nicotine dependence. Herein we report a significant association between rs1800497 and heavy smoking (OR=0.48 95% CI: 0.25--0.93; p=0.03) and number of cigarettes smoked per day (OR=0.16, 95%CI: 0.16--1.11; p=0.05). Additionally, rs1800497, rs6274, rs6276 were associated with quit attempts while rs6279 was associated with cumulative clinical nicotine dependence.;To determine the relationship between dopamine and DRD2 in vitro , DRD2 expression and cAMP activity was measured in SHSY5Y (D1-like) and Y-79 (D2-like cells) cell lines. The results indicate that, the D1-like cells are more sensitive to the effects of dopamine than the Y-79 cells. These data provide evidence for an association between DRD2 SNPs and nicotine dependence in African Americans and substantiates the hypothesis that, dopamine deficiency is a possible explanation for nicotine dependence observed in former and current smokers. Investigation of clinically-defined symptoms for nicotine dependence may further our understanding of genetic determinants that contribute to the biology of nicotine dependence and tobacco cessation in African-Americans smokers.