miR-196a2 中常见多态性与腰臀比的关联以及 miR-1908 与血脂和血糖的关联。

The association of common polymorphisms in miR-196a2 with waist to hip ratio and miR-1908 with serum lipid and glucose.

作者信息

Ghanbari Mohsen, Sedaghat Sanaz, de Looper Hans W J, Hofman Albert, Erkeland Stefan J, Franco Oscar H, Dehghan Abbas

机构信息

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

出版信息

Obesity (Silver Spring). 2015 Feb;23(2):495-503. doi: 10.1002/oby.20975. Epub 2014 Dec 31.

DOI:10.1002/oby.20975

PMID:25557604

Abstract

OBJECTIVE

MicroRNAs (miRNAs) have been implicated in the regulation of cardiometabolic disorders. Given the crucial role of miRNAs in gene expression, genetic variation within miRNA genes is expected to affect miRNA function and substantially contribute to disease risk.

METHODS

2,320 variants in miRNA-encoding sequences were systematically retrieved, and their associations with 17 cardiometabolic traits/diseases were investigated, using genome-wide association studies (GWAS) on glycemic indices, anthropometric measures, lipid traits, blood pressure, coronary artery disease, and type 2 diabetes. Next, target genes of the identified miRNAs that may mediate their effect on the phenotypes were examined. Furthermore, trans- expression quantitative trait loci analysis and luciferase reporter assay to provide functional evidence for our findings were performed.

RESULTS

rs11614913:C/T in miR-196a2 was associated with waist to hip ratio (P-value=1.7 × 10(-5) , β = 0.023). Two target genes, SFMBT1 and HOXC8, which may mediate this association were identfied, and they were shown experimentally as direct targets of miR-196a2. Moreover, rs174561:C/T in miR-1908 was found to be associated with total cholesterol (P-value=6.5 × 10(-16) , β=0.044), LDL-cholesterol (P-value=4.3 × 10(-18) , β=0.049), HDL-cholesterol (P-value=1.7 × 10(-6) , β=0.026), triglyceride (P-value=7.8 × 10(-14) , β=0.038), and fasting glucose (P-value=4.3 × 10(-10) , β=0.02). In addition, a number of miR-1908 target genes were highlighted as potential mediators.

CONCLUSIONS

The results indicated miRNA-dependent regulation of fat distribution by miR-196a2 and of lipid metabolism by miR-1908.

摘要

目的

微小RNA（miRNA）已被证明参与心脏代谢紊乱的调节。鉴于miRNA在基因表达中的关键作用，miRNA基因内的遗传变异有望影响miRNA功能，并在很大程度上导致疾病风险。

方法

系统检索了2320个miRNA编码序列中的变异，并使用全基因组关联研究（GWAS）对血糖指数、人体测量指标、血脂特征、血压、冠状动脉疾病和2型糖尿病等17种心脏代谢特征/疾病进行研究，以探讨它们之间的关联。接下来，研究了可能介导miRNA对表型影响的已鉴定miRNA的靶基因。此外，进行了反式表达定量性状位点分析和荧光素酶报告基因检测，为我们的研究结果提供功能证据。

结果

miR-196a2中的rs11614913:C/T与腰臀比相关（P值 = 1.7×10⁻⁵，β = 0.023）。鉴定出两个可能介导这种关联的靶基因SFMBT1和HOXC8，并通过实验证明它们是miR-196a2的直接靶标。此外，发现miR-1908中的rs174561:C/T与总胆固醇（P值 = 6.5×10⁻¹⁶，β = 0.044）、低密度脂蛋白胆固醇（P值 = 4.3×10⁻¹⁸，β = 0.049）、高密度脂蛋白胆固醇（P值 = 1.7×10⁻⁶，β = 0.026）、甘油三酯（P值 = 7.8×10⁻¹⁴，β = 0.038）和空腹血糖（P值 = 4.3×10⁻¹⁰，β = 0.02）相关。此外，一些miR-1908靶基因被确定为潜在的介导因子。