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Published on: June 15, 2018
rs2910164 Polymorphism Confers a Decreased Risk for Pulmonary Hypertension by Compromising the Processing of
Haitao Liu1, Mai Chen, Feng Wu
1Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Objective:
To identify the association between rs2910164 polymorphism and development of pulmonary hypertension, as well as underlying molecular mechanism.
Methods And Results:
281 patients diagnosed with pulmonary hypertension and 325 normal controls were recruited, and rs2910164 genotype was determined in each participant: As a result, the rs2910164 polymorphism was significantly associated with the development of pulmonary hypertension after adjusting some potential confounding factors. Additionally, lung tissue samples were obtained from 39 patients who received surgical intervention for lung cancer, and mRNA and protein expression levels of miR-146a, COX-2 and PGI2 production were examined. Furthermore, we confirmed COX-2 is a target of miR-146a in pulmonary smooth muscle cells, and identified a differentially expressed miR-146a and COX-2 in each rs2910164 genotype group. We observed a significant association between rs2910164 polymorphism and the levels of either COX-2 or PGI2 using real-time PCR and western blot. In conclusion, the results of this study demonstrate that the rs2910164 CC and GC genotype is associated with a decreased risk of pulmonary hypertension, which could be attributed to defective miRNA processing and compromised ability to inhibit production of COX-2 and PGI2.
Insights
The rs2910164 polymorphism is linked to a lower risk of pulmonary hypertension. This association may stem from impaired microRNA-146a (miRNA) processing, affecting cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) production.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Research
Background:
- Pulmonary hypertension (PH) is a complex disease with significant morbidity and mortality.
- Genetic factors, including single nucleotide polymorphisms (SNPs), are implicated in PH development.
- The role of microRNA-146a (miR-146a) and its downstream targets in PH pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the association between the rs2910164 polymorphism and the risk of developing pulmonary hypertension.
- To explore the underlying molecular mechanisms involving miR-146a, cyclooxygenase-2 (COX-2), and prostaglandin I2 (PGI2) in PH.
- To determine the functional relationship between rs2910164 genotype and miR-146a/COX-2 expression levels.
Main Methods:
- Case-control study including 281 PH patients and 325 healthy controls.
- Genotyping of the rs2910164 polymorphism using participant DNA.
- Analysis of miR-146a and COX-2 mRNA and protein expression in lung tissue samples (n=39) via real-time PCR and Western blot.
- Functional validation of COX-2 as a miR-146a target in pulmonary smooth muscle cells.
Main Results:
- The rs2910164 polymorphism showed a significant association with pulmonary hypertension risk after adjusting for confounding factors.
- Individuals with CC and GC genotypes for rs2910164 exhibited a decreased risk of developing PH.
- Differential expression of miR-146a and COX-2 was observed across different rs2910164 genotype groups.
- A significant correlation was found between rs2910164 polymorphism and the levels of COX-2 and PGI2 production.
Conclusions:
- The rs2910164 CC and GC genotypes are associated with a reduced risk of pulmonary hypertension.
- This protective effect may be mediated by enhanced miRNA processing, leading to better inhibition of COX-2 and PGI2.
- The findings highlight the rs2910164 polymorphism as a potential genetic marker for PH susceptibility and provide insights into its molecular underpinnings.
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