Fukutake Masaaki, Hishimoto Akitoyo, Nishiguchi Naoki, Nushida Hideyuki, Ueno Yasuhiro, Shirakawa Osamu, Maeda Kiyoshi
Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-Ku, Kobe, 650-0017, Japan.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1428-33. doi: 10.1016/j.pnpbp.2008.02.003. Epub 2008 Feb 16.
It has been suggested that noradrenergic system abnormalities are involved in suicide. Postmortem brain studies have shown that molecular and functional alterations in alpha2A-adrenergic receptor-induced signal transduction are associated with suicide and depression. Recently, a single nucleotide polymorphism (SNP) within a coding region of the alpha2A-adrenergic receptor gene (ADRA2A), which results in an Asn-to-Lys change at amino acid 251 (N251K), has been implicated in susceptibility to suicide in Caucasians. The aim of our study is to determine whether genetic variants of the ADRA2A gene are also associated with suicide in a Japanese population.
Three SNPs, C-1291G, N251K and rs3750625C/A, and one insertion/deletion polymorphism in the ADRA2A gene were genotyped in 184 completed suicides and 221 control subjects with the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.
Neither variation of the N251K SNP nor the insertion/deletion polymorphism was found in our Japanese samples. The C-1291G SNP in the promoter region was found to be significantly associated with suicide in females (P=0.043 and 0.013 for genotypic and allelic comparisons, respectively). One of the common haplotypes, CC of C-1291G and rs3750625C/A, was also associated with suicide in females (P=0.015). These associations were also significant in the female violent suicide victims (P=0.009 and 0.009 for allelic and CC haplotypic comparisons, respectively). Although the significance was nominal, it was maintained even after correction for multiple comparisons. By contrast, neither of these two SNPs showed any association with violent and/or non-violent suicide in males.
Our results raise the possibility that promoter genetic variation in the ADRA2A gene is associated with either suicide or violent suicide in females.
有人提出去甲肾上腺素能系统异常与自杀有关。死后大脑研究表明，α2A肾上腺素能受体诱导的信号转导中的分子和功能改变与自杀和抑郁症有关。最近，α2A肾上腺素能受体基因（ADRA2A）编码区内的一个单核苷酸多态性（SNP），导致第251位氨基酸由天冬酰胺变为赖氨酸（N251K），被认为与白种人的自杀易感性有关。我们研究的目的是确定ADRA2A基因的遗传变异在日本人群中是否也与自杀有关。
采用聚合酶链反应和限制性片段长度多态性（PCR-RFLP）方法，对184例自杀身亡者和221例对照者的ADRA2A基因中的三个SNP，即C-1291G、N251K和rs3750625C/A，以及一个插入/缺失多态性进行基因分型。
在我们的日本样本中未发现N251K SNP的变异或插入/缺失多态性。发现启动子区域的C-1291G SNP与女性自杀显著相关（基因型和等位基因比较的P值分别为0.043和0.013）。常见单倍型之一，即C-1291G和rs3750625C/A的CC型，也与女性自杀有关（P=0.015）。这些关联在女性暴力自杀受害者中也很显著（等位基因和CC单倍型比较的P值分别为0.009和0.009）。尽管显著性为名义上的，但即使在进行多重比较校正后仍保持显著。相比之下，这两个SNP在男性暴力和/或非暴力自杀中均未显示出任何关联。
我们的结果提示，ADRA2A基因启动子区的遗传变异可能与女性自杀或暴力自杀有关。
