Li Ming D, Lou Xiang-Yang, Chen Guobo, Ma Jennie Z, Elston Robert C
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia 22911, USA.
Biol Psychiatry. 2008 Dec 1;64(11):951-7. doi: 10.1016/j.biopsych.2008.04.026. Epub 2008 Jun 4.
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.
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 Fagerström Test for Nicotine Dependence score of 4.0 or more and 348 unrelated nonsmokers.
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).
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.
流行病学数据表明，尼古丁依赖（ND）受基因、环境因素及其相互作用的影响。尽管分子实验已证明脑源性神经营养因子（BDNF）通过神经营养性酪氨酸激酶受体2（NTRK2）发挥其功能，且α4（CHRNA4）和β2（CHRNB2）亚基都需要形成功能性含α4β2的烟碱型受体（nAChRs），但尚无研究报告表明这四个基因之间存在影响ND的基因 - 基因相互作用。
为了确定这四个基因之间是否存在基因 - 基因相互作用，我们在一个病例对照样本中对CHRNA4和BDNF的六个单核苷酸多态性（SNP）、NTRK2的九个SNP以及CHRNB2的四个SNP进行了基因分型，该样本包含275名Fagerström尼古丁依赖测试评分≥ 4.0的不相关吸烟者和348名不相关非吸烟者。
通过使用我们最近开发的广义多因素降维算法，我们发现CHRNA4和CHRNB2、CHRNA4和NTRK2、CHRNB2和NTRK2以及BDNF和NTRK2这几对基因之间存在高度显著的基因 - 基因相互作用（所有四对基因的p <.01），并且CHRNA4和BDNF之间在ND上存在显著的基因 - 基因相互作用（p =.031）。未检测到CHRNB2和BDNF之间存在显著相互作用（p =.068）。
我们的研究首次提供了这四个基因之间存在影响ND的基因 - 基因相互作用的证据。尽管在先前一些关于ND的关联研究中，单独的CHRNB2与ND无显著关联，但我们发现它通过与CHRNA4和NTRK2相互作用来影响ND。
