血浆外泌体来源的 microRNAs 表达谱分析及在高胆固醇血症和 ATP 敏感性钾通道变异 rs1799858 相互作用下的生物信息学分析
Plasma exosome-derived microRNAs expression profiling and bioinformatics analysis under cross-talk between increased low-density lipoprotein cholesterol level and ATP-sensitive potassium channels variant rs1799858.
机构信息
Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, 1 Panfu Road, Guangzhou, 510180, China.
Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
出版信息
J Transl Med. 2020 Dec 3;18(1):459. doi: 10.1186/s12967-020-02639-8.
BACKGROUND
Exosome-derived microRNAs (exo-miRs) as messengers play important roles, in the cross-talk between genetic [ATP-sensitive potassium channels (KATP) genetic variant rs1799858] and environmental [elevated serum low-density lipoprotein cholesterol (LDL-C) level] factors, but the plasma exo-miRs expression profile and its role in biological processes from genotype to phenotype remain unclear.
METHODS
A total of 14 subjects with increased LDL-C serum levels (≥ 1.8 mmol/L) were enrolled in the study. The KATP rs1799858 was genotyped by the Sequenom MassARRAY system. The plasma exo-miRs expression profile was identified by next-generation sequencing.
RESULTS
64 exo-miRs were significantly differentially expressed (DE), among which 44 exo-miRs were up-regulated and 20 exo-miRs were down-regulated in those subjects carrying T-allele (TT + CT) of rs1799858 compared to those carrying CC genotype. The top 20 up-regulated DE-exo-miRs were miR-378 family, miR-320 family, miR-208 family, miR-483-5p, miR-22-3p, miR-490-3p, miR-6515-5p, miR-31-5p, miR-210-3p, miR-17-3p, miR-6807-5p, miR-497-5p, miR-33a-5p, miR-3611 and miR-126-5p. The top 20 down-regulated DE-exo-miRs were let-7 family, miR-221/222 family, miR-619-5p, miR-6780a-5p, miR-641, miR-200a-5p, miR-581, miR-605-3p, miR-548ar-3p, miR-135a-3p, miR-451b, miR-509-3-5p, miR-4664-3p and miR-224-5p. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were subsequently implemented to identify the top 10 DE-exo-miRs related specific target genes and signaling pathways. Only 5 DE-exo-miRs were validated by qRT-PCR as follows: miR-31-5p, miR-378d, miR-619-5p, miR-320a-3p and let-7a-5p (all P < 0.05).
CONCLUSION
These results firstly indicated the plasma exo-miRs expression profile bridging the link between genotype (KATP rs1799858) and phenotype (higher LDL-C serum level), these 5 DE-exo-miRs may be potential target intermediates for molecular intervention points.
背景
外泌体来源的 microRNAs（exo-miRs）作为信使，在遗传[三磷酸腺苷敏感性钾通道（KATP）基因变异 rs1799858]和环境[血清低密度脂蛋白胆固醇水平升高（LDL-C）]因素之间的相互作用中发挥重要作用，但从基因型到表型的血浆外泌体 miR 表达谱及其在生物学过程中的作用仍不清楚。
方法
共纳入 14 名血清 LDL-C 水平升高（≥1.8mmol/L）的受试者。采用 Sequenom MassARRAY 系统对 KATP rs1799858 进行基因分型。通过下一代测序鉴定血浆外泌体 miR 表达谱。
结果
64 个外泌体 miR 差异表达（DE）明显，其中 rs1799858 携带 T 等位基因（TT+CT）的受试者与携带 CC 基因型的受试者相比，44 个外泌体 miR 上调，20 个外泌体 miR 下调。前 20 个上调的 DE-exo-miRs 是 miR-378 家族、miR-320 家族、miR-208 家族、miR-483-5p、miR-22-3p、miR-490-3p、miR-6515-5p、miR-31-5p、miR-210-3p、miR-17-3p、miR-6807-5p、miR-497-5p、miR-33a-5p、miR-3611 和 miR-126-5p。前 20 个下调的 DE-exo-miRs 是 let-7 家族、miR-221/222 家族、miR-619-5p、miR-6780a-5p、miR-641、miR-200a-5p、miR-581、miR-605-3p、miR-548ar-3p、miR-135a-3p、miR-451b、miR-509-3-5p、miR-4664-3p 和 miR-224-5p。随后进行了基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析，以确定与前 10 个 DE-exo-miRs 相关的特定靶基因和信号通路。仅通过 qRT-PCR 验证了 5 个 DE-exo-miRs：miR-31-5p、miR-378d、miR-619-5p、miR-320a-3p 和 let-7a-5p（均 P<0.05）。
结论
这些结果首次表明血浆外泌体 miR 表达谱连接了基因型（KATP rs1799858）和表型（更高的 LDL-C 血清水平）之间的联系，这 5 个 DE-exo-miRs 可能是潜在的分子干预靶点。
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