Susceptibility to chronic thromboembolic pulmonary hypertension may be conferred by miR-759 via its targeted interaction with polymorphic fibrinogen alpha gene
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A deletion/insertion (Del/Ins) polymorphism of 28 base pairs (bp) in the 3′ untranslated region (UTR) of fibrinogen alpha gene (FGA) was associated with thromboembolic diseases, but the underlying mechanisms remain unknown. Computational predication reveals that the 28 bp polymorphic fragment is complementary to the sequence of a microRNA, miR-759. In this study, we aim to investigate the association and implicated mechanisms between FGA polymorphisms and the susceptibility to chronic thromboembolic pulmonary hypertension (CTEPH). The Del/Ins polymorphism was analyzed in 190 patients with CTEPH and 628 controls. The FGA 3′UTR and miR-759 interaction was investigated using luciferase assay and quantitative RT-PCR method. Expression of miR-759 and FGA in human tissues was investigated by RT-PCR. The results reveal that the allele frequency of Ins was significantly higher in the patients than in the controls (55.8 vs. 47.1%, P = 0.003, odds ratio = 1.42, 95% confidence interval: 1.13–1.79). Both miR-759 and FGA were expressed in human liver. Co-transfection of miR-759 decreased the expression and mRNA stability of reporter gene containing the FGA 3′UTR. The effect of miR-759 was stronger on the Ins allele than on the Del allele. These observations suggest that the expression of FGA was regulated by miR-759 through its interaction at the polymorphic 3′UTR sequence, which was associated with the susceptibility to CTEPH.
The authors are grateful to Drs. S. Kominami, N. Nakanishi, H. Tomoike, M. Sakuma, and K. Shirato for their contributions in the collection of clinical data and blood samples from the CTEPH patients. This study was supported in part by Grant-in-Aids from the Ministry of Education, Science, Sports, Culture and Technology (MEXT) of Japan, the program of Founding Research Centers for Emerging and Reemerging Infection Disease supported by MEXT, Japan, research grants from the Ministry of Health, Labor and Welfare, Japan, including those for Research Committee of Intractable Respiratory Failure and for the Cardiovascular Disease, grants for Japan-Korea collaboration research program and Japan-Indo collaboration research program from Japan Society for the Promotion of Science, and research grants from The Institute of Seizon and Life Sciences. This work was also supported in part by the follow-up grants provided from the Tokyo Medical and Dental University.
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