Gene-Gene Interactions Among CHRNA4, CHRNB2, BDNF, and NTRK2 in Nicotine Dependence

Background: Epidemiological data indicate that nicotine dependence (ND) are influenced by genes, environmental factors, and their interactions. Although it has been documented from molecular experiments that brain-derived neurotrophic factor (BDNF) exerts its functions via neurotrophic tyrosine kinase receptor 2 (NTRK2) and both alpha 4 (CHRNA4) and beta 2 (CHRNB2) subunits are required to form functional alpha 4 beta 2-containing nicotinic receptors (nAChRs), no study is reported demonstrating that there exist gene-gene interactions among the four genes in affecting ND. Methods: To determine if gene-gene interactions exist among the four genes, we genotyped six single nucleotide polymorphisms (SNPs) for CHRNA4 and BDNF, nine SNPs for NTRK2, and four SNPs for CHRNB2 in a case-control sample containing 275 unrelated smokers with a Fagerstrom Test for Nicotine Dependence score of 4.0 or more and 348 unrelated nonsmokers. Results: By using a generalized multifactor dimensionality reduction algorithm recently developed by us, we found highly significant gene-gene interactions for the gene pairs of CHRNA4 and CHRNB2, CHRNA4 and NTRK2, CHRNB2 and NTRK2, and BDNF and NTRK2 (p <.01 for all four gene pairs) and significant gene-gene interaction between CHRNA4 and BDNF (p =.031) on ND. No significant interaction was detected for CHRNB2 and BDNF (p =.068). Conclusions: Our study provides first evidence on the presence of gene-gene interaction among the four genes in affecting ND. Although CHRNB2 alone was not significantly associated with ND in several previously reported association studies on ND, we found it affects ND through interactions with CHRNA4 and NTRK2.