A Study On Polymorphisms Of Elastin Gene And Pathogenesis In Chinese Han Patients With Isolated Systolic Hypertension

BackgroudIsolated systolic hypertension of the eldly was a subtype of Essential hypertension and characteristiced by elevated systolic and pulse pressure,high mortality and high morbility.Even through,ISH has been an outcome of co-contribution of environment and inherit factors,unfortunately,the pathogenesis of ISH has not been fully understood.With the development of molecular genetics, the effect of inherit factor on the Essential Hypertension morbility has been emphasized.As yet,150 candidate genes for EH had been studied,which involved in renin-angiotensin-aldosterone system(RAAS),sympathetic nervous system(SNS), low-cerebral ganglion-master gland-axon,endothelin(ET),natriuretic peptide, KAL-kinin system,steroid hormone(STH),prostaglandin(PG),growth factor(GF), hormone,skeleton protein,adhesion molecule,intracellular messenger,lipide metabolism,glycometabolism,apolipoprotein(APO),ion channel,and so on.But no gene variant has been confirmed to be associated with EH.Owing to characteristic of the indefinite heredity model,high genetic heterogeneity,low penetrance,more genes participated,single gene effect feeble for the EH as some polygene diseases,and relatively low samples for the studies,it was all in the day's work that the studies arrived at different results.Because of the EH including some subtypes,it is difficult to get confirmedly information about the gene association with EH,and may be as a breakthrough to interpret EH pathogenesis to chose a certain subtype.ISH was characterized by high artery stiffness and low artery compliance,it is reported that all the factors involved in promoting artery stiffness which might be lead to ISH.It had been confirmed that the change of structure and function of elastin located in the large artery media could caused artery stiffness,and some reports about the contributions of elastin to angio-development and cardiovascular diseases revoked our interest in studying elastin gene.a deletion involving 7q11.23 that results in hemizygosity of the elastin gene has been identified as the mechanism responsible for the Williams and Buren syndrome,which is characterized by supravalvular aortic stenosis,hypertension or peripheral stenoses.Li et al had reported that elastin is an essential determinant of arterial morphogenesis,the characterization of mice haploinsufficient for elastin(Eln^+/-) revealed a role for elastin in the formation of vessel wall structure.The arteries of Eln^+/- mice exhibited thinner elastic lamellae and an increased number of smooth muscle cell layers.Most interestingly,these identical changes have been observed in the arteries of patients with SVAS.D'Armiento J demonstrated that mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene.due to mechanical changes in the vessel wall,these animals exhibit increased mean arterial pressures.The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.Some studies had also reported that elastin gene polymorphisms were associated with artery stiffness,Hanon O et al.identified the relationship between the Ser422Gly polymorphism of the elastin gene in exon 16(rs2071307) and the distensibility of elastic arteries.9 Interestingly,Iwai N et al.revealed the association of the rs34208922 polymorphism with hypertension and pulse wave velocity.10 Furthermore,Akagawa H et al.reported that SNP(rs34208922) is involved in the reduction of elastin mRNA transcripts in vitro and ex vivo.11 Recently,elastin has also been suggested to be a potential candidate gene for familial intracranial aneurysms(IAs) 12,13and subarachnoid hemorrhages(SAH),14 which we also found defects in the internal elastic lamina.As a result,ELN may be considered as a functional candidate gene for ISH.Pulse wave velocity(PWV) is a known marker of arterial stiffness and defined as the speed in which the pulse wave travels along the length of an artery.It was reported that at any given SBP,brachial-ankle Pulse wave velocity(baPWV) decreased with the increasing DBP,and at any given DBP,baPWV increased with the increasing SBP in Chinese patients with essential hypertension.Also,baPWV was higher in patients with ISH compared to age-matched healthy individuals.Serum C-reactive protein(CRP) is known as a marker of inflammation and some studies have shown that inflammation is independently associated with arterial stiffness and PWV.Alternatively,inflammation may induce structural changes in the arterial wall by altering the balance between elastin breakdown and synthesis.Therefore,the functional candidate gene for ISH may be associated with baPWV and CRP.The main purpose of this study was to evaluate the possible association between polymorphism of the ELN gene and ISH,baPWV,CRP and IMT.Part oneThe study of Pulse Wave Velocity and Heart Rate Variability in patients with Isolated Systolic HypertensionObjective To investigate the characteristics of Pulse Wave Velocity(PWV) and Heart Rate Variability(HRV) and the effect of them on estimating the Cardiovascular Risk in patients with isolated systolic hypertension(ISH).Methods 89 ISH patients and 98 systolic-diastolic hypertension patients admitted in our hospital were taken carotid-radial PWV(crPWV),carotid-femoral PWV(cfPWV) and HRV(total power(TP),very low frequency(VLF),low frequency(LF),high frequency(HF) and LF/HF,analyzed by 5min short-term frequency domain) by SUN-8800,and then survey the difference of them between the ISH patients and systolic-diastolic hypertension patients and the correlation of PWV with HRV. Furtherly,89 ISH patients were divided into four groups:low risk group(n=3), moderate risk group(n=17),high risk group(n=35) and very high risk group(n=34) according to the degree of Total Cardiovascular Risk and investigate the difference of cfPWV,crPWV and HRV among the four groups and the correlation of cfPWV, crPWV and HRV with the degree of Total Cardiovascular Risk. Results The cfPWV of ISH group is significantly higher than that of sys-diastolic hypertension group(ISH:399.6±48.2cm/s vs sys-diastolic hypertension: 374.3±39.7cm/s,P＜0.05],but there is no difference in crPWV between ISH group and sys-diastolic hypertension group(ISH:371.5±37.5cm/s VS sys-diastolic hypertension:363.5±31.5cm/s,P＞0.05).The VLF,LF and LF/HF in ISH group are markedly higher than those in sys-diastolic hypertension group(ISH:4.35±1.07logms², 3.28±0.86logms² and 1.19±0.53 vs sys-diastolic hypertension:3.78±0.82logms², 2.93±0.59logms³ and 0.89±0.43,P＜0.05),while the TP and HF are evidently lower than those in sys-diastolic hypertension group(ISH:4.76±1.03logms², 2.75±1.43logms² vs sys-diastolic hypertension:5.15±1.36logms,3.27±1.57logms², P＜0.05).The cfPWV is positively related with the VLFand LF and negatively related with the TP and HF(r=0.563,r=0.549,r=-0.542 and r=-0.571,respectively,P＜0.05) but the crPWV is not related with VLF,LF,TP and HF.The cfPWV and cfPWV are markedly positive correlated with the degree of the Total Cardiovascular Risk(r_s=0.765,r_s=0.563,P＜0.05),with the increase of degree of the Cardiovascular Risk,the cfPWV is significantly increased(P＜0.05),but the crPWV is not significantly increased(P＞0.05).The VLF,LF and LF/HF are markedly positive correlated with the degree of the Total Cardiovascular Risk(r_s=0.438,r_s=0.479 and r_s=0.126,P＜0.05),adversely,the TP and HF are dramaticly negative correlated with the degree of the Total Cardiovascular Risk(r_s=-0.467,r_s=-0.421,P＜0.05), with the increase of degree of the Cardiovascular Risk,the VLF,LF and LF/HF are significantly increased,but the TP and HF are markedly decreased(P＜0.01).Conclusion The cfPWV,VLF,LF and LF/HF are significantly increased,however, the TP and HF markedly decreased in ISH patients.cfPWV and HRV should be as important clinic indexs to evaluate ISH cardiovascular risk and the effect of ISH treatment. Part twoThe Association of Pulse Wave Velocity and Microalbuminuria in Older Patients with Isolated Systolic HypertensionObjective To investigate the effects of change of pulse wave velocity(PWV) on microalbuminuria(MAU) and analyze the association between PWV and MAU in patients with Isolated systolic hypertension.Methods Carotid-radial PWV(crPWV) and carotid-femoral PWV(cfPWV) were determined in 265 patients with Isolated systolic hypertension.The participants were assigned to groups with microalbuminuria and with normoalbuminuria,and their characteristics,cfPWV,crPWV and the morbidity of cardiovascular incidence were compared.We also examined the association between MAU and cfPWV,crPWV using linear correlation and logistic regression analyses.Results 149 microalbuminuria participants had significantly higher cfPWV,crPWV and morbidity of cardiovascular incidence than those with normoalbuminuria.After adjusted the age,systolic blood pressure,diastolic blood pressure and pulse pressure, the Odds Ratio of MAU were increased with the increasing of cfPWV and crPWV among the quartiles of cfPWV and crPWV(P for trend=0.017,P for trend=0.025). Linear correlation analyses showed that cfPWV and crPWV were markedly positive correlated with the 24 hours urinary albumin excretion(r=0.875,P=0.001;r=0.763, P=0.017),multiple logistic regression analyses showed that cfPWV and crPWV were independently associated with MAU(P=0.015,P=0.023) after adjustment for age, systolic blood pressure,diastolic blood pressure and pulse pressure.Conclusion MAU was independently associated with cfPWV and crPWV,cfPWV and crPWV were the important affected factors of MAU. Part threeA Study on Polymorphisms of Elastin Gene in Chinese Han Patients with Isolated Systolic HypertensionBackground.Elastin(ELN) is mainly located in the internal elastic lamina of large arteries.Degradation of elastin is expected to induce large vessel stiffness,which could lead to elderly systolic hypertension.Recent studies have shown the polymorphism of ELN is associated with stiffness of elastic arteries and elevated blood pressure,however,there are no further studies on isolated systolic hypertension.Methods.We identified the genotype of the ELN gene in 358 patients with isolated systolic hypertension(ISH),413 essential hypertension patients with elevated diastolic blood pressure(EH) and 244 age-matched normotensive(NT) controls for 5 SNPs and detected the baPWV,CRP and IMT for these patients.Results.ISH was statistically significant in association with SNP rs34208922(A allele frequency was 0.068 in ISH patients,0.036 in EH patients and 0.014 in NT controls;P＜0.001,P_corr＜0.005) and possibly with SNP rs2071307(A allele frequency was 0.103 in ISH patients,0.079 in EH patients and 0.047 in NT controls; P=0.002,P_corr=0.01),however,the A allele frequency was not different between ISH patients and EH patients.In addition,baPWV and CRP were significantly associated with SNP rs34208922 and rs2071307.The other three SNPs were not significantly associated with ISH,baPWV,CRP or IMT.Haplotypes of TGGTA and TGAT-were also significantly associated with ISH(P=0.0001,P_corr=0.0021;P=0.0023, P_corr=0.0483).Conclusions.Variants within the elastin gene are associated with increased risk of ISH and aortic stiffness in the Chinese Han population.