Manzardo Ann M, Gunewardena Sumedha, Wang Kun, Butler Merlin G
Department of Psychiatry and Behavioral Sciences , University of Kansas School of Medicine, Kansas City, Kansas.
Alcohol Clin Exp Res. 2014 Jun;38(6):1594-601. doi: 10.1111/acer.12429. Epub 2014 May 30.
Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males.
Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA).
Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN), and signaling (e.g., RASGRP3, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease and development including cellular assembly and organization impacting on psychological disorders.
Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation, and signaling that targets white matter of the brain.
酒精滥用与细胞和生化紊乱有关，这些紊乱会影响蛋白质和核酸合成、大脑发育、功能及行为反应。为进一步明确酒精中毒的遗传影响以及饮酒对基因表达的作用，我们使用高灵敏度外显子微阵列检测酒精成瘾者和对照男性的人类额叶皮质中的mRNA表达。
从7名成年酒精成瘾者（6名男性，1名女性，平均年龄49岁）和7名匹配对照的背外侧前额叶皮质（dlPFC；布罗德曼9区）中分离信使核糖核酸。按照标准程序进行Affymetrix人类外显子1.0 ST阵列检测，并在基因水平分析结果。使用定量逆转录聚合酶链反应验证微阵列结果，并通过Ingenuity通路分析（IPA）对受干扰基因的本体进行表征。
观察到参与细胞黏附（如CTNNA3、ITGA2）、转运（如TF、ABCA8）、神经系统发育（如LRP2、UGT8、GLDN）和信号传导（如RASGRP3、LGR5）且影响脂质和髓磷脂合成（如ASPA、ENPP2、KLK6）的基因的mRNA表达降低。IPA识别出与神经疾病和发育相关的网络功能紊乱，包括影响心理障碍的细胞组装和组织。
我们关于酒精中毒的数据支持与神经元生长、分化及靶向脑白质的信号传导相关的dlPFC mRNA表达降低。
