| Background and Purpose:High-mobility group box 1 protein(HMGB1), as a DAMP, is a pro-inflammatory cytokine, which can be released into the extracellular space from immunologically competent cells when exposed to the stimulation of microbial products and other danger signals, and acts as a proinflammatory cytokine by activating pattern recognition receptors(PRRs), including Toll-like receptor 4(TLR4) and receptor for advanced glycation end products(AGER) with oxidative injury. The AGEs induced oxidative damage signal pathway is associated with endothelial dysfunction. Animal study proved that HMGB1 contributed to the pathogenesis of experimental pulmonary hypertension via activation of TLR4, and another research suggested that with serum HMGB1 level increasing, the risk of CAD in non-diabetic and type 2 diabetic patients increased significantly. TGF-beta receptor-associated protein 1(TGFBRAP1) is a cytoplasmic protein shown to bind to TGFBR1 and helped Smad4 to participate in vascular development and remodeling mainly through TGF-beta/Smad Signaling. In diabetic animal models, Anti-AGER Antibody could inhibit the up-regulation of TGF-β and fiber deposition in peritoneum. Several studies showed that TGF-beta/Smad Signaling made a role in hematopoietic development, and TLR4-Myd88-NFκB pathway regulated hemopoietic stem cell by Notch signaling. We could infer: firstly, there is an associationbetween endothelial dysfunction and vascular remodeling, secondly, inflammatory signaling might be associated with fetal hematopoietic stem cell, thirdly, there may be an interaction between the AGEs induced oxidative damage signal pathway and TGF-beta/Smad Signaling pathway. The purpose of this study is to investigate whether the HMGB1 gene of AGEs induced oxidative damage signal pathway and TGFBRAP1 gene of TGF-beta/Smad Signaling pathway contribute genetic susceptibility to blood pressure regulation, hypertension(HT), and to evaluate the genetic effect of HMGB1 and TGFBRAP1 on drug treatment of patient with HT, and to explore the effect of blood pressure by child psychological behavior and wheather psychological behavior and HMGB1 gene polymorphism had interactive effects on the elevation of blood pressure.Methods:In children and adolescents population, a case-control study comprising 270 cases(elevation of blood pressure) abd 1514 controls(normal blood pressure) was conducted, and information about demographic characteristics, blood blood pressure and serum biochemicals was collected. In the adult population, a case-control study comprising 2012 hypertension cases and 2210 controls was conducted, and information about demographic characteristics, blood blood pressure and serum biochemicals was collected. Furthermore, a validation research in a children population was used to replicate the association generated from adult population. Among controls, genotype frequencies for each SNP were tested by Fisher’s exact χ2 test using the program Hardy-Weinberg equilibrium(HWE). Unpaired Student’s t-test was used to test the differences of all quantitative variables presented as the means±SD between cases and controls. Six tagging single nucleotide polymorphisms(tag SNPs) of HMGB1 gene and TGFBRAP1 gene were selected by linkage disequilibrium(LD) analysis and functional prediction. Qualitative variables, the allele and genotype frequency distributions between cases and controls were compared by the two-sided Chi-square(χ2) test.Two-tailed P value of <0.05 was defined to be statistically significant. Untraditional logistic regression model was used to adjust confounding factor for HT and general linear model(GLM) was applied to compare blood pressure levels and plasma TGF-beta1 levels between genotypes in cases and controls. 780 patients with hypertension were recruited by taking compound reserpine, Zhen Ju Jiang Ya Tablet and Jiang Ya Tablet.Results:Single locus analysis for the six tag SNPs of HMGB1 and TGFBRAP1 with HT didn’t show significant association for HT and no no significant haplotype constructed of the three tag SNPs with HT was identified comparing with the reference Haplotype. Further stratification analysis found that rs2249825 was significantly associated with HT in ≥55 years groups, ORs(95%CI) of additive model and dominant model were 1.208(1.029-1.417) and 1.212(1.020-1.441), and P values were 0.021 and 0.029 respectively. Quantitative trait analysis indicated that diastolic blood pressure(DBP) had a linear decrease with the variations of rs2249825 in both untreated HT group(P=0.002) and control group(P=0.034) respectively after adjusted for covariates. Also, there is significant difference of DBP between the genotypes of rs1045411(P=0.015). In hypertensive taking compound reserpine, after adjusting the confounding factors, diastolic blood pressure(DBP) linearly decreased with the variation(T>C) of rs1412125(P=0.040). Quantitative trait analysis indicated that DBP had a linear decrease with the variations of rs2679860(P=0.005) after adjustment for confounding factor. And normally distributed square root of TGF-beta1(pg/ml) had a linear increased with the variations of rs2679860(P=0.042) after adjusting covariates. In children and adolescents population, multiple logistic regression analysis showed that femail, elevation of TG, overweight and obesity are risk factors of elevation of blood pressure; rural population, high-grade in primary school are protective factors ofelevation of blood pressure. Further quantitative trait analysis for the Z-scores of SBP and DBP in children indicated that, in city children, there is significant difference of Z-scores of SBP and DBP between the genotypes of rs1045411(P=0.043,0.006), and for rs2679860, AA genotype carriers had a lower Z-scores of DBP than the AG+GG genotype carriers(P=0.040) after adjusted for covariates. But the direction of this genetic effect was opposite of that in the adult population. In male children, rs1045411 was significantly associated with elevation of blood pressure(EBP), ORs(95%CI) of additive model were 0.656(0.445-0.968) and P values were 0.034. In female hypertensive taking Zhen Ju Jiang Ya Tablet,after adjusting the covariant, systolic blood pressure(SBP) significantly decreased with the variation(G>A) of rs1045411 and the variation(C>G) of rs2249825 respectively(P=0.044 and 0.043). In age≥55 hypertensive taking Jiang Ya Tablet, different genotypes were significantly different after adjusting the covariant(P=0.048).Conclusions:Our finding suggests that rs2249825 of HMGB1 genetic polymorphisms are significantly associated with HT and DBP, and the genetic effect on HT is modulated by age. HMGB1 gene might affect the antihypertensive effect of compound reserpine, Zhen Ju Jiang Ya Tablet and Jiang Ya Tablet. And in senile population, age modulated the impact of rs2249825 on the therapeutic effect of Jiang Ya Tablet. Meanwhile, mental behavior problems modified the interaction between the variations of rs1045411 and EBP. Psychological behavior problems made a significant role in the elevated blood pressure in children and adolescents population. TGFBRAP1 genetic polymorphisms are significantly associated with DBP variation and plasma levels of TGF-beta1. The variation of rs2679860 might influence the direct modulatory effect of TGF-beta1 on the blood pressure by regulating the plasma levels of TGF-beta1. |
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