Detection of Genetic Association and a Functional Polymorphism of Dynamin 1 Gene with Nicotine Dependence in European and African Americans

Abstract

Although it has been documented that dynamin 1 gene (DNM1) is significantly modulated by nicotine in animal models, its association with nicotine dependence (ND) in human population remained to be unexplored. To determine whether DNM1 is associated with ND, in this study, we genotyped seven single-nucleotide polymorphisms (SNPs) within this gene in 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP-based association analysis revealed a significant association of SNP rs3003609 with Smoking Quantity (SQ; P = 0.0031) and Heaviness of Smoking Index (HSI; P = 0.0042) in the EA sample. Furthermore, our haplotype-based association analyses indicated that haplotypes T-G-T, formed by rs2502731-rs2229917-rs3003609 (at a frequency of 54%), G-T-A, formed by rs2229917-rs3003609-rs16930313 (at a frequency of 52%), and T-A-G, formed by rs3003609-rs16930313-rs7022174 (at a frequency of 52%) are significantly associated with SQ (Z = −2.44~−2.92; P = 0.015~0.0055) and HSI (Z = −2.52~−2.67; P = 0.012~0.0076) in the EA sample. In the AA sample, another haplotype, G-T-A, formed by rs7875406-rs2502731-rs2229917, at a frequency of 12% was significantly associated with SQ (Z = −2.58; P = 0.0098). Finally, by using in vitro gene expression assays, we demonstrated that the T allele of rs3003609 in the exon 9 of DNM1 significantly decreases the expression of dynamin 1, by 27.1% at the mRNA and 22.0% at the protein level, suggesting that rs3003609 represents a functional polymorphism affecting DNM1 expression and may partly contributed to the observed association of the gene with ND in our samples. Taken together, our findings indicate that dynamin 1 is likely involved in the etiology of ND and represents a plausible candidate for further investigation in independent samples.