VIP Gene Variants Related To Idiopathic Pulmonary Arterial Hypertension In Han Nationality Of Chinese Population

Idiopathic pulmonary arterial hypertension(IPAH) is a rare but fatal disease characterized by sustained pulmonary vascular resistance and mean pulmonary artery pressure,which result in right heart failure and death.The pathogenesis of IPAH is still unknown.Many research suggested that the excessive proliferation and inhibitory apoptosis of pulmonary artery smooth muscle cells(PASMC) was correlated with IPAH.Excessive proliferation of PASMC results in pulmonary vasoconstriction, increased thickness of pulmonary arteries and pulmonary vascular remodeling.A variety of studies have linked vasoactive intestinal peptide(VIP) to IPAH.It was reported that VIP can inhibit the proliferation of PASMC and accelerate its apoptosis. Mice with target deletion of VIP gene show moderate pulmonary hypertension.VIP serum level in IPAH patient is lower than that in normal subject.In this study,we hypothesize that VIP gene variants result in the lower expression of VIP,which may account for the pathogenesis and development of IPAH.We sought consecutively 81 unrelated IPAH patients from 2007 to 2008 at Fuwai hospital.250 control individuals were selected from the communities.VIP gene variants were screened by direct sequencing and VIP serum level were determined by ELISA.Hemodynamic data of all IPAH patients were obtained by right heart catheterization.The variant g.8129T→Cin 3'UTR of exon 7 was found to be the only variant in the exons of VIP gene.The frequency of VIP g.8129T→C of IPAH patients(40.7%, n=33) was significantly higher than that(15.2%,n=38) of control subjects.The VIP serum level of patients was significantly lower than that of control subjects.Although gene variants in 3'UTR do not alter the encoding of amino acid residues,they can impact the binding of microRNA to 3'UTR and expression of VIE Moreover,there was marked difference in VIP serum level and hemodynamic data between IPAH patients with and without this VIP gene variant.The variant g.8129T→C in exon 7 of VIP gene was correlated with the clinical phenotype of lower VIP serum level,higher mean pulmonary artery pressure and pulmonary vascular resistance in IPAH patients comparing to those in patients without this variant.VIP gene variant g.8129 T→C may be one of the risk factors in the pathogenesis of IPAH. Idiopathic pulmonary arterial hypertension(IPAH) is rare but fatal disease, which may be developed by genetic and environmental factors.The pathogenesis of IPAH is still unknown.Many research suggested that the excessive proliferation and inhibitory apoptosis of pulmonary artery smooth muscle cells(PASMC) was correlated with IPAH.The main abnormal change of IPAH is remodeling of pulmonary vascular system and sustained pulmonary vasoconstriction.[Ca²⁺]_cyt in PASMC is the main factor of the trigger of pulmonary vasoconstriction and stimulation to proliferation of PASMC.In the study,we investigate the relevance of genetic alterations in the Kv1.5 channel gene(KCNA5) to the development of IPAH in Chinese Han nationality.We sought consecutively 86 unrelated IPAH patients from 2007 to 2008 at Fuwai hospital.250 control individuals were selected from the communities.KCNA5 gene variants were screened by direct sequencing.Hemodynamic data of all IPAH patients were obtained by right heart catheterization.The variant g.862C→G in the coding region was found to be the only variant, which frequency is significantly different between IPAH patients and control subjects.. The frequency of KCNA5 C-862G of IPAH patients(43%,n=36) was significantly higher than that(6%,n=16) of control subjects.This gene variant in exon can alter the encoding of amino acid residues;they can impact the expression of KCNA5. Moreover,there was marked difference in hemodynamic data between IPAH patients with and without this KCNA5 gene variant.The variant g.862C→G in coding region of KCNA5 gene was correlated with the clinical phenotype of pulmonary vasoconstriction,higher mean pulmonary artery pressure and pulmonary vascular resistance in IPAH patients comparing to those in patients without this variant.KCNA5 gene variant g.862 C→G may be one of the risk factors in the pathogenesis of IPAH and Genetic variant KCNA5 C-862G may alter the expression and/or function of Kv1.5 channel,which may be associated with IPAH of phenotype.