Beta-arrestins 1 and 2 are associated with nicotine dependence in European American smokers

On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the beta-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample.