The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
C
C
Wu
Y
Y
Gong
A
A
Sun
Y
Y
Zhang
C
C
Zhang
W
W
Zhang
G
G
Zhao
Y
Y
Zou
J
J
Ge
D020413:3' Untranslated Regions; D000368:Aged; D001054:Apolipoproteins A / Q000097:blood; D044466:Asian People; D016022:Case-Control Studies; D002681:China; D008076:Cholesterol, HDL / Q000097:blood; D019295:Computational Biology; D003327:Coronary Disease / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*
D020413:3' Untranslated Regions; D001054:Apolipoproteins A; D008076:Cholesterol, HDL; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)