| Background and objectivesCardiovascular disease is the leading cause of death for adults in the world.Hypertension has been proved the primary and independent modifiable risk factor forstroke and coronary heart disease (CHD) so that controlling hypertension is one of themost effective ways to prevent cardiovascular disease. And it is of great significanceto study the pathogenesis of hypertension.As the major basis in pathologic process of EH, large artery stiffening,peripheral resistance increasing caused by endothelial dysfunction and small arteryremodeling have been proved the primary agent for blood pressure increase or evenorgan impairment. Transforming growth factor-β1can regulate cell proliferation anddifferentiation, embryogenesis. And we conducted studies of TGF-beta1pathwaygenes in the pathogenesis of hypertension and further screening of blood pressure,drug antihypertensive effect of genetic variants of the TGF-beta1pathway genes andtheir transcriptional regulation of micro RNA (miRNA), to further elucidate themolecular mechanism of this complex disease hypertension and candidate target forscreening of sensitive drugs.Animal experiments reported that some genetic defects of elastic fibrescomponents such as Emilin1and Fibrillin1, which are important regulator forTGF-β1signal pathway, are accompanied by abnormal vessel structure and arterystiffening and remodeling. Our previous study reported the significant association ofEmilin1gene and Fibrillin1gene and hypertension. This led us to further research thedevelopment and remodeling of artery in EH. Here we further evaluate theassociation between TGFBR2gene and target miR518gene involving in thebiological function of TGF-β1signal pathway and hypertension, blood pressure andefficacy of antihypertensive. With the purpose of exploring the relationship between the development and remodeling of artery and EH, we pursued series of progresses onthe development and remodeling of blood vessel and selected two candidate genes ofTGFBR2gene and target miR518gene, which proved being involved in the TGF-βsignal pathway. In the present study, we applied a case-control study and selectedtagSNPs which optimized for potential biological function to evaluate the associationof the two genes with hypertension and explore potential gene-environmentinteractions.Subjects and MethodsAll the subjects aged40-85years old were recruited from a rural Han populationin two townships near20kilometers apart in Yixing country by the epidemiologicalcluster sampling approach. In the present study,2012hypertensive cases with systolicblood pressure (SBP)≥140mmHg, and/or diastolic blood pressure (DBP)≥90mmHg,or currently administering anti-hypertensive medication were selected. Patients with aclinical history of secondary hypertension, coronary heart disease, kidney disease anddiabetes were excluded.2210age-and sex-matched normotensives with SBP <140mmHg and DBP <90mmHg were selected as controls from the same target studypopulation.We searched SNPs covered TGFBR2gene upstream5kb to test and selectedtagger SNPs (tagSNPs) from the data of Chinese Han population in Beijing, China(CHB) in HapMap (HapMap Data Rel24/phase II Nov08, on NCBI B36assembly,dbSNP b126). All7tagSNPs in TGFBR2gene were selected with minor allelefrequency (MAF)≥0.05and r2>0.8according to the linkage disequilibrium (LD)values and were to test in the association study. And target miR518gene was selectedrs7256241(MAF>0.05) to test in all subjects.ResultsThe results indicated that there was no association between TGFBR2gene andmiR518gene and hypertension and further stratified analysis by sex, age, drinkingand smoking suggested that rs9850060was associated with hypertension in drinking,OR (95%CI) of additive and dominated model were0.779(0.615-0.987) and 0.739(0.558-0.980) respectively. Rs3773661was associated with hypertension inmale, OR (95%CI) of additive and dominated model were0.844(0.726-0.981) and0.807(0.664-0.980) respectively. The recessive model of rs11709624and additivemodel of rs1155705showed statistical significance in <55years groups populationand no smoking population, the ORs (95%CI) were0.673(0.462-0.981) and0.896(0.803-1.000) respectively. But, the P value after Bonferroni correction didn’t reachthe statistical significance.Genetic risk score analysis indicated that GRS>P75group decrease the risk ofhypertension compared to GRS≤P25group, the OR (95%CI) was0.78(0.657-0.927)and P value was4.67×10-3, and Bonferroni correction reach the significant leval. Inuntreated hypertensive patients, GRS was liner increased with SBP, Partial regressioncoefficient was0.212(P=0.038) after adjusted for confounding factors.Quantitative trait analysis showed that rs7256241of miR518significantlyassociated with diastolic blood pressure (DBP) in control subjects (P=0.002) and thatwas further replicated in children population (P=0.036).In female hypertensive taking compound reserpine, systolic blood pressure (SBP)linearly increased with the variation (G>C) of rs3773661(P=0.004) and DBP wasdifferent with the variation (T>G) of rs7256241(P=0.001).In hypertensive taking Zhen Ju Jiang Ya Tablet, both SBP and DBP linearlydecreased with the variations (C>T) of rs749794respectively (P=0.004and0.048).SBP linearly decreased with the variation (G>A) of rs1155705(P=0.007) and thevariation (G>C) of rs11709624(P=0.042), but increased with the variations (C>T) ofrs1036096(P=0.027) in male respectively.In male hypertensive taking Jiang Ya Tablet, SBP linearly increased with thevariation of (G>C) of rs11709624(P=0.007), DBP linearly increased with thevariations of rs1155705(P=0.031) but decreased with the variation of rs7256241(P=0.035) respectively.Serum TGF-β1level was different between cases and controls (P=0.007), andsTGF-β1was linearly decreased with rs7256241in control group (P=0.046). ConclusionsThese findings suggest that rs9850060, rs3773661, rs11709624and rs1155705were associated with hypertension and the effects might be affected by age, gender,smoking and drinking status. GRS>P75group decrease the risk of hypertensioncompared to GRS≤P25group, and GRS was liner increased with SBP in untreatedhypertensive patients. Rs7256241was associated with sTGF-β1in control and SBP inhealthy adults and adolecesents respectively. And TGFBR2gene and miR518genemight affect the antihypertensive effect of compound reserpine, Zhen Ju Jiang YaTablet and Jiang Ya Tablet. |
PDF Full Text Request