Csala Iren, Dome Peter, Lazary Judit
Szentágothai János Idegtudományi Doktori Iskola, Semmelweis Egyetem, Budapest, Hungary.
Neuropsychopharmacol Hung. 2017 Dec;19(4):189-196.
Backgorund: There is accumulating evidence on the association between the cholinergic system and nicotine dependence (ND) in the literature and the bidirectional relationship of ND and depression. However, the molecular background of the development of ND and related affective phenotype is not clear.
We recruited 255 tretament-seeking smokers into our study. For phenotyping assessments we used the Fagerstrom Nicotine Dependence Test; The Minnessotta Nicotine Withdrawal Scale; the Zung Self-Rating Depression Scale and the Parental Bonding Instrument. DNA was isolated from buccal mucosa sample and CHRNA4 and CHRNB2 gene SNPs were genotyped with MassArray Sequenom techniques. For statistical analyses ANOVA test, Mann-Whitney U test, linear regression, two-step cluster analyses and hapscore tests were performed.
Two-step cluster analysis revealed 3 well-differentiated subgroups among smokers based on phenotypic characteristics. One subgroup was associated with the highest withdrawal and depressive scores. Frequency of the risk haplotype of CHRNA4 was significantly higher in this subgroup (p=0.019). Further, lifetime prevalence of major depression was also significantly higher in this subgroup. Besides, CHRNB2 gén variants showed a significant interacting effect with maternal bonding style on suicide thoughts (p=0.005).
Our results confirmed the genetic effect of CHRNA4 and CHRNB2 on smoking-related depression. These findings suggest that a genetically vulnerable subgroup can be distinguished among smokers and this subphenotype is more prone to withdrawal and depressive symptoms. Our data suggest that suicidal risk depends on both CHRNB2 gene variants and maternal bonding style. Pharmacogenetic concerns of CHRNA4 and CHRNB2 genes might be significant considering suicide as side effect of quitting therapy. Further pharmacogenetic investigations are requierd to clarify this possibility.
背景：文献中关于胆碱能系统与尼古丁依赖（ND）之间的关联以及ND与抑郁之间的双向关系有越来越多的证据。然而，ND及相关情感表型发展的分子背景尚不清楚。
我们招募了255名寻求治疗的吸烟者参与研究。对于表型评估，我们使用了法格斯特龙尼古丁依赖测试、明尼苏达尼古丁戒断量表、zung自评抑郁量表和父母教养方式问卷。从颊黏膜样本中分离DNA，并用MassArray Sequenom技术对CHRNA4和CHRNB2基因的单核苷酸多态性进行基因分型。进行统计分析时，采用了方差分析、曼-惠特尼U检验、线性回归、两步聚类分析和单倍型评分测试。
两步聚类分析显示，吸烟者根据表型特征可分为3个明显不同的亚组。其中一个亚组与最高的戒断和抑郁评分相关。该亚组中CHRNA4风险单倍型的频率显著更高（p = 0.019）。此外，该亚组中重度抑郁症的终生患病率也显著更高。此外，CHRNB2基因变异与母亲教养方式对自杀念头有显著的交互作用（p = 0.005）。
我们的结果证实了CHRNA4和CHRNB2对吸烟相关抑郁的遗传影响。这些发现表明，吸烟者中可区分出一个遗传易感性亚组，该亚表型更容易出现戒断和抑郁症状。我们的数据表明，自杀风险取决于CHRNB2基因变异和母亲教养方式。考虑到自杀是戒烟治疗的副作用，CHRNA4和CHRNB2基因的药物遗传学问题可能很重要。需要进一步的药物遗传学研究来阐明这种可能性。
