Abstract
Considering the predominant role of rare variants of the Bone morphogenetic protein 9 (BMP9) gene in the occurrence of idiopathic pulmonary arterial hypertension (IPAH), here we conducted a case-control study, together with functional validation, to explore the relationships between variants of the BMP9 gene and development of IPAH. We found minor alleles of rs3740297 (OR: 0.72, 95% CI: 0.59-0.87, P=7.77×10-5) and rs7923671 (OR: 0.76, 95% CI: 0.62-0.93, P=0.009) were significantly associated with decreased risk of IPAH. Minor alleles of rs3740297 and rs7923671 were significantly associated with increased plasma level of BMP9 in both IPAH cases and controls (P<0.001). An allele of rs7923671 showed higher relative luciferase activity compared to that containing G allele (P<0.001). Mechanism exploration found that pulmonary artery smooth muscle cells (PASMC) cell line transfected with rs3740297 C allele construct, miR-149 mimic, and antagomir miR-149 showed more sensitive change of the relative luciferase activity and BMP9 expression. This means minor allele T of rs3740297 could significantly decrease susceptibility of IPAH in Chinese population, possibly by increasing BMP9 expression through losing a miR-149 binding site. Our study provides evidence for genetic associations between two specific variants in the BMP9 gene and plasma level of BMP9, occurrence of IPAH.
Highlights
Pulmonary arterial hypertension (PAH), a severe vasculopathy characterized by progressive narrowing and obliteration of the pulmonary arterioles, resulted in heart failure and premature death, and had raised the public concerns [1,2,3]
Among the five SNPs, we found minor alleles of rs3740297 (OR: 0.72, 95% confidence intervals (CIs): 0.59-0.87, P=7.77×10-5) and rs7923671 (OR: 0.76, 95% CI: 0.620.93, P=0.009) were significantly associated with decreased risk of idiopathic PAH (IPAH)
We found minor alleles of rs3740297 and rs7923671 were significantly associated with increased plasma level of Bone morphogenetic protein 9 (BMP9) in both IPAH cases and controls (P
Summary
Pulmonary arterial hypertension (PAH), a severe vasculopathy characterized by progressive narrowing and obliteration of the pulmonary arterioles, resulted in heart failure and premature death, and had raised the public concerns [1,2,3]. Growing evidence revealed multiple genetic and environmental mechanisms contributed to PAH development, including the incapacitation or mutation of the bone morphogenetic protein receptor type-2 (BMPR2) gene, epigenetic abnormality, or the sex hormone imbalance, the exact pathogenesis still remains unclear [6]. These factors could only explain a fraction of PAH cases, suggesting additional PAH genes awaiting exploration [6, 7]. Wang et al [9] conducted an exome-wide gene-based burden analysis and reported that the rare coding mutations in BMP9 gene occurred in 6.7% of idiopathic PAH (IPAH) cases, ranking this gene second to the BMPR2 gene. Considering the predominant role of rare variants of the BMP9 gene in www.aging-us.com
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