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首页> 外文期刊>Cell cycle >SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways.
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SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways.

机译：SNP引导的16种常见人类疾病的microRNA图（MirMaps）可以确定一种可逆转核输入和炎症小体途径转录异常的临床可行疗法。

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摘要

We report the results of a disease phenocode analysis interrogating the relationships between structural features and gene expression patterns of disease-linked SNPs, microRNAs and mRNAs of protein-coding genes in association to phenotypes of 16 major human disorders, which was enabled by multiple independent studies of up to 451,012 combined samples including 194,258 disease cases and 256,754 controls. SNP sequence homology-guided microRNA maps (MirMaps) identify consensus components of a disease phenocode consisting of 81 SNPs and 17 microRNAs. microRNAs of the consensus set are associated with at least 4 common human diseases (range 4 to 7 diseases) and manifest sequence homology/complementarity to at least 4 distinct disease-linked SNPs (range 4 to 14 SNPs). Nearly all microRNAs (15 of 17; 88%) of the consensus set has potential protein-coding mRNA targets among the principal components of the nuclear import pathway (NIP) and/or inflammasome pathways including KPNA1, NLRP1 (NALP1) and NLRP3 (NALP3)genes. Analysis of expression profiling experiments of peripheral blood mononuclear cells (PBMC) demonstrates statistically significant KPNA1-, NLRP1- and NLRP3-gene expression phenotypes associated with human genotypes of Crohn's disease (CD), Huntington's disease (HD) and rheumatoid arthritis (RA) populations. Unexpectedly, microarray analysis of PBMC from patients treated with chloroquine reveals a reversal of disease-linked KPNA1-, NLRP1- and NLRP3-gene expression phenotypes, implying that chloroquine could serve as a readily clinically available drug for targeted correction of identified aberrations. We conclude that genetically-defined malfunctions of the NIP and inflammasome pathways are likely to contribute to pathogenesis of multiple common human disorders and PBMC-based genetic tests may be useful for monitoring the individual's response to therapy. Prescription of chloroquine, an FDA-approved drug which is widely utilized for treatment of malaria, RA and systemic lupus erythematosus (SLE), may havea therapeutic value in clinical management of a large spectrum of human disorders.
机译：我们报告了疾病表型分析的结果，该结果询问了与16种主要人类疾病的表型相关的疾病相关的SNPs，microRNA和蛋白编码基因的mRNA和结构特征与基因表达模式之间的关系。多达451,012个合并样本，包括194,258个疾病病例和256,754个对照。 SNP序列同源性指导的microRNA图（MirMaps）可以确定由81个SNP和17个microRNA组成的疾病表型的共有成分。共有序列的微小RNA与至少4种人类常见疾病（4至7种疾病）相关，并且与至少4种不同疾病相关的SNP（4至14种SNP）表现出序列同源性/互补性。共识集中几乎所有的microRNA（17个中的15个; 88％）在核输入途径（NIP）和/或炎症小体途径（包括KPNA1，NLRP1（NALP1）和NLRP3（NALP3） ）基因。对外周血单个核细胞（PBMC）的表达谱实验的分析表明，与人类克罗恩病（CD），亨廷顿病（HD）和类风湿关节炎（RA）基因型相关的KPNA1，NLRP1和NLRP3基因表达表型具有统计学意义。出乎意料的是，对用氯喹治疗的患者进行的PBMC的微阵列分析显示，与疾病相关的KPNA1，NLRP1和NLRP3基因表达表型发生了逆转，这意味着氯喹可以作为一种易于临床使用的药物，用于有针对性地纠正已识别的像差。我们得出的结论是，NIP和炎症小体途径的遗传学定义上的功能障碍可能会导致多种常见人类疾病的发病机理，而基于PBMC的基因测试可能有助于监测患者对治疗的反应。氯喹是美国食品与药物管理局（FDA）批准的药物，广泛用于治疗疟疾，RA和系统性红斑狼疮（SLE），对许多人类疾病的临床治疗具有治疗价值。

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