The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding.
BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.