Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Nutr Metab Cardiovasc Dis. 2013 Jul;23(7):693-8. doi: 10.1016/j.numecd.2012.02.009. Epub 2012 May 28.
Abnormal functioning of 5,10-methylenetetrahydrofolate reductase (MTHFR) enhances the risk for coronary heart disease (CHD). Here, we tested whether a single-nucleotide polymorphism (SNP) located in the 3' untranslated region (UTR) of MTHFR was associated with CHD susceptibility by affecting microRNAs binding.
We first analyzed in silico the SNPs localized in the 3' UTR of MTHFR for their ability to modify miRNA binding. We observed that rs4846049 (G > T) was a potential candidate SNP to modulate miRNAs:MTHFR mRNA complex, with the greatest changed binding free energy for has-miR-149. Based on luciferase analysis, hsa-miR-149 inhibited the activity of the reporter vector carrying -T allele, but not -G allele. We further conducted a case-control study (654 vs 455) in a Chinese Han population. rs4846049 was significantly associated with increased risk for CHD. In addition, the T allele was associated with decreased levels of HDL-cholesterol and apoA. Finally, we observed a reduced MTHFR protein level in peripheral blood mononuclear cells of CHD patients with TT carriers compared to GG carriers of rs4846049.
Our results suggest that rs4846049 (G > T) of MTHFR is associated with increased risk for CHD. We also identified a potentially pathogenetic mechanism of SNP-modified posttranscriptional gene regulation by miRNAs to MTHFR.
5,10-亚甲基四氢叶酸还原酶（MTHFR）功能异常会增加冠心病（CHD）的风险。在这里，我们通过检测 SNP 是否影响 miRNA 的结合来测试位于 MTHFR 3'非翻译区（UTR）的 SNP 是否与 CHD 的易感性相关。
我们首先对 MTHFR 3'UTR 中的 SNP 进行了计算机分析，以研究其改变 miRNA 结合的能力。我们观察到 rs4846049（G>T）是一个潜在的候选 SNP，可以调节 miRNA：MTHFR mRNA 复合物，对 has-miR-149 的结合自由能改变最大。基于荧光素酶分析，hsa-miR-149 抑制了携带-T 等位基因的报告载体的活性，但不抑制携带-G 等位基因的报告载体的活性。我们进一步在中国汉族人群中进行了病例对照研究（654 例 vs 455 例）。rs4846049 与 CHD 风险增加显著相关。此外，T 等位基因与 HDL-胆固醇和载脂蛋白 A 水平降低相关。最后，我们观察到与 rs4846049 的 GG 携带者相比，TT 携带者的冠心病患者外周血单个核细胞中的 MTHFR 蛋白水平降低。
我们的研究结果表明，MTHFR 的 rs4846049（G>T）与 CHD 的风险增加相关。我们还确定了 SNP 通过 miRNA 对 MTHFR 进行的潜在致病的转录后基因调控机制。
