微小核醣核酸基因miR-34a和miR-432上單一核苷酸多型性與精神分裂症之相關性研究

微小核醣核酸 (microRNA) 為一重要的基因表現調控因子，其表現量可能在許多疾病中扮演重要角色。另外，許多文獻指出，微小核醣核酸基因上的單一核苷酸多型性 (single nucleotide polymorphism)，為影響其表現量的因素之一。在之前研究中，有兩個微小核醣核酸基因miR-34a與miR-432的表現量，顯著在精神分裂症病人跟健康對照組身上有差異。故本研究欲探討此兩個候選基因上的單一核苷酸多型性與精神分裂症之相關性，以及這些單一核苷酸多型性與微小核醣核酸表現量的關聯性。研究樣本來自2007至2009年收案的90名台大醫院精神分裂症病人及60名健康對照。收集其周邊血液後，針對兩個候選基因，在其先驅微小核糖核酸 (precursor miRNA) 序列上下500個核苷酸的範圍，使用ABI 3730做定序。在微小核糖核酸表現量部分，則使用ABI 7900即時反轉錄聚合酶連鎖反應 (real-time RT-PCR) 測得。定序後，在我們的樣本中找到6個變異，包括在miR-432基因上的2個已知的單一核苷酸多型性，以及在miR-34a基因上的4個新變異。在單一核苷酸多型性之基因型跟疾病狀態相關性的分析中，雖然都未達到顯著相關性，但仍可看出在rs41286564，精神分裂症病人帶有較多的C對偶基因。在單一核苷酸多型性rs41286564基因型與微小核糖核酸表現量的分析，雖然仍未達到顯著差異的結果，但在精神分裂症病人中可觀察到帶有G對偶基因者，有較低miR-432表現量的趨勢存在。在有限的結果下，小樣本的研究仍提供一些在微小核糖核酸基因上的單一核苷酸多型性與精神分裂症間的線索，未來可用更全面的方式進一步探究微小核糖核酸基因在精神分裂症病因扮演的角色。

關鍵字

精神分裂症；微小核糖核酸；生成過程；單一核苷酸多型性

並列摘要

Recent studies have indicated aberrant microRNA (miRNA) expressions detected from both the blood and brains are associated with schizophrenia. Single nucleotide polymorphisms (SNPs) located at miRNA genes were linked to different levels of miRNA expression. Some studies suggested that genetic variants around miRNA genes miR-34a and miR-432 were associated with schizophrenia. This study aimed to investigate whether SNPs within two candidate miRNA genes are associated with schizophrenia, and explore the correlation between such SNP and the expression level of the corresponding miRNA. Participants consisted of 90 schizophrenia patients recruited from National Taiwan University Hospital and 60 healthy controls from university staffs, students, and community volunteers during 2007-2009. Their venous blood was collected for DNA extraction. Sequencing was used to search for variants within the segment of +/- 500 bp of precursor miRNA genes (pre-miRNAs). In addition, the total RNA was extracted from mononuclear leukocytes. The corresponding cDNAs were obtained by reverse transcription PCR and the RNA expression levels were measured using quantitative real-time PCR. There were 6 variants indicated after screening. Two in miR-432 gene had been reported as SNPs (rs185297997 and rs41286564), and the rest in miR-34a were novel variants. Genetic association analysis showed no statistically significant association between any miRNA SNPs and schizophrenia though higher frequency of C allele of SNP rs41286564 in schizophrenia patients was revealed. In correlation analysis, there was no significant result though the effect of G allele was presented to reduce miR-432 expression level in schizophrenia patients. Further convergent analysis for miRNA biogenesis should be tested in investigating the etiology of schizophrenia.

並列關鍵字

schizophrenia ； microRNA ； biogenesis ； SNPs

參考文獻

Bartel, D. P. 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116, 281-97.

Beveridge, N. J., Gardiner E., Carroll A. P., Tooney P. A. & Cairns M. J. 2010. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry, 15, 1176-89.

Burmistrova, O. A., Goltsov A. Y., Abramova L. I., Kaleda V. G., Orlova V. A. & Rogaev E. I. 2007. MicroRNA in schizophrenia: Genetic and expression analysis of miR-130b (22q11). Biochemistry (Moscow), 72, 578-582.

Chen, W. J., Liu S. K., Chang C. J., Lien Y. J., Chang Y. H. & Hwu H. G. 1998. Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry, 155, 1214-20.

Feng, J., Sun G., Yan J., Noltner K., Li W., Buzin C. H., Longmate J., Heston L. L., Rossi J. & Sommer S. S. 2009. Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One, 4, e6121.

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微小核醣核酸基因miR-34a和miR-432上單一核苷酸多型性與精神分裂症之相關性研究

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