Essential Hypertension Susceptibility Gene Number Of Point Of Interaction Between The Math Model

Background and Objects:Essential hypertension is recognized as a common complex disorder depending on a mosaic of many genes each with a minute contribution and under the influence of multiple gene-gene and gene-environment interactions.Despite the completion of human genome project and progression of functional genomics,current endeavors in unraveling the genetic makeup of human hypertension have not automatically bathed the patient's bedside in a helpful new light.So far,finding and confirming how many genes and which genetic determinants are actually involved in the development of essential hypertension remain an interpretive challenge.The present study focused on a rather controversial issue;that is,the influence of genetic variation of the renin-angiotensin-aldosterone system(RAAS) in the development and progression of essential hypertension by aid of the collaboration of molecular biology,genetics and biostatistics.The selection of candidate genes in RAAS is founded on strong biological hints.In this study,we evaluated five candidate genes of RAAS,viz.renin,angiotensinogen(AGT),angiotensin converting enzyme(ACE), bradykinin B2 receptor(BKB2R) and aldosterone synthase(CYP11B2) genes.Evidence is mounting suggesting the strong genetic susceptibility of these genes or encoded proteins to essential hypertension.However,the results regarding the genetic contribution of these genes to essential hypertension have been inconsistent and even contradictory.To address this issue and provide more information,we selected 13 common polymorphisms evenly interspersed in these 5 genes and explored the individual and interactive associations of these polymorphisms with the risk of essential hypertension in a northern Han Chinese population.Methods:Our study was a population-based case-control study design.All subjects are of Han Chinese descent recruited from the Fangshan district,which is located in the southwest region of Beijing.A total of 2459 subjects were recruited;of them there were 1305 hypertensive patients and 1154 healthy controls.This Fangshan population offers some important advantages for hypertension study,including high prevalence of hypertension (16.8%),low prevalence of treatment,low divorce rate and limited mobility.Genotyping was performed using polymerase chain reaction(PCR),restriction fragment length polymorphism(RFLP) and DNA sequencing techniques.Data were analyzed using receiver operating characteristic curve,single-locus,haplotype and synergistic analyses.Results:In single-locus analysis,the genotype distributions of AGT T174M and BKB2R C-58T polymorphisms and the genotype and allele distributions of ACE A-240T,I/D,A2350G, BKB2R±9bp,CYP11B2 C-344T and K173R polymorphisms differed statistically between hypertensives and normotensives,while other genotype and allele distributions showed no differences(all P＞0.05).Our haplotype analysis focusing on polymorphisms on single genes indicated that the overall haplotypes of AGT,ACE and CYP11B2 showed strong associations with essential hypertension,even after the rigorous Bonferroni correction,which further suggested that the polymorphisms in one gene might contribute interactively.For example,from the eight combinations of the three polymorphisms in ACE,haplotype inspection further identified the potential risky and protective haplotypes in this population,such as the risky haplotypes A-I-A and A-D-A(in the order of A-240T,I/D and A2350G in ACE), and the protective haplotypes T-I-A and T-D-G.Finally,using MDR method,we selected the final best model including AGT M235T, ACE A-240T,I/D,G2350T,BKB2R C-58T and CYP11B2 K173R polymorphisms by evaluating the magnitude of cross-validation consistency and prediction error simultaneously.In particularly,the interaction information analysis indicated that polymorphisms A-240T and I/D,as well as polymorphisms M235T and C-58T had strong synergistic effects.Moreover,the interrelationship between these two sets might be independent or additive.Conclusions:In this study,we focused on a large-scale of Han Chinese population to explore the association of the thirteen polymorphisms in five candidate genes of RAAS,both individually,as haplotypes and in synergistic patterns,with essential hypertension and added strong evidence for the synergistic interactions of the RAAS gene polymorphisms. Further research is required to elucidate the relationship between these polymorphisms and hypertension,and mechanisms of RAAS and hypertension.