Rahikainen Anna-Liina, Palo Jukka U, Haukka Jari, Sajantila Antti
Departments of Forensic Medicine.
Forensic Genetics Unit, National Institute for Health and Welfare, Helsinki, Finland.
Pharmacogenet Genomics. 2018 Apr;28(4):99-106. doi: 10.1097/FPC.0000000000000328.
Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved.
The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated.
All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis.
No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed.
Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance of sex-based segregation in pharmacogenetics studies.
外排转运蛋白——通透性糖蛋白（P - gp）的基因变异最近被发现与已完成的暴力自杀以及暴力自杀未遂有关。由于抑郁症是自杀的已知危险因素，且许多抗抑郁药是P - gp的底物，因此有人推测可能涉及抗抑郁治疗反应不足或不良副作用。
本研究旨在调查P - gp编码基因ABCB1与使用西酞普兰的已完成自杀者之间是否存在关联。此外，还评估了性别和自杀方式（暴力与非暴力）的影响。
研究人群中的所有病例，349例已完成自杀的受害者和284例对照者，在尸检毒理学药物筛查中均显示抗抑郁药西酞普兰呈阳性。通过TaqMan基因分型测定法确定ABCB1 1236C>T、2677G>T/A和3435C>T多态性。使用PHASE软件从基因型数据构建单倍型。通过逻辑回归分析检验死亡方式与ABCB1单倍型之间的关联。
自杀组和对照组之间在ABCB1等位基因或基因型频率上未观察到统计学上的显著差异。然而，ABCB1 1236T - 2677T - 3435T单倍型与使用西酞普兰的女性已完成自杀有关（比值比：2.23；95%置信区间：1.22 - 4.07；P = 0.009）。按自杀方法分层后，这种关联在致命中毒中出现（比值比：2.51；95%置信区间：1.29 - 4.87；P = 0.007）。在其他组中，未观察到统计学上的显著关联。
我们的结果表明，具有ABCB1 1236T - 2677T - 3435T的使用西酞普兰的女性更容易受到药物不良反应的影响，因为这种单倍型在使用西酞普兰的女性非暴力自杀中更为富集。尽管这一观察结果背后的生物学机制尚不清楚，但结果提供了另一个例子，说明在药物遗传学研究中基于性别的分类的重要性。
