Insulin-Like Growth Factor Binding Protein-1 And-3 Contribute Genetic Susceptibility To Essential Hypertension

Objective:Essential hypertension is a complex trait,and both genetic and environmental determinants contribute to its pathogenesis..Previous studies have showed that the Insulin-like growth factor-1?IGF-1?axis is involved in the development of hypertension..The aim of this study is to analyze the relationship between IGF binding protein-1?IGFBP-1?and IGFBP-3 genetic variants and hypertension,and to explore the molecular mechanism of hypertension pathogenesis.Methods:The study was designed as a community-based epidemiological survey method.In 2009,two community residents were examined in southern of Jiangsu.We selected 2012 hypertensive cases and 2210 healthy controls from this population.The subjects were followed up for an average of 5.16 years and new incidences of hypertension were collected from the healthy controls during the period.Three single-nucleotide polymorphisms?SNPs?in IGFBP-1?rs1065780,rs2453853,rs1874479?and four SNPs in IGFBP-3?rs3110697,rs13223993,rs2132572,rs2453839?were selected for TaqMan genotyping in4222 subjects.Multiple logistic regression and Cox regression were performed to evaluate the association of these seven SNPs with hypertension in case control study and follow-up study.The further stratification association was analyzed by age,gender,smoking and drinking factors.Association between haplotype and hypertension was performed using HAPSTATA3.0 software.A general linear model was used to analyze the relationship between blood pressure quantitative traits and genotypes.The IGFBP-1 and IGFBP-3 protein levels did not follow Gaussian distributions after logarithm and square root transition,so IGFBP-1 and IGFBP-3 protein levels between hypertension group and control group and genotypes were compared by nonparametric test.A general linear model was used to analyze the relationship between blood pressure quantitative traits and genotypes.Results:In the case-control study,rs2132572 and rs3110697 at IGFBP-3 were significantly associated with increased hypertension,and the ORs?95%CIs?of the dominant model were 1.153?1.021-1.303?and 1.218?1.072-1.384?,and the P values were 0.022 and 0.002,respectively.After adjustment for age,gender,TC,TG,LDL-C,HDL-C,GLU,BMI,smoking status,and drinking status,the association remained statistically significant.In smokers,comparing with those with IGFBP-1 rs1874479 G allele,the hypertension risk of A allele was 1.278 fold.In the follow-up study,Cox regression analysis showed that rs2132572 was significantly associated with hypertension.The incidence risk of hypertension in the TT genotype was 1.57 times as high as that of the CT and CC genotypes?P=0.034?.The association was still statistically significant after adjustment for age,gender,TC,TG,HDL-C,LDL-C,T2DM,BMI,smoking and drinking.Stratified analysis showed that in males,the hypertension incidence risk in the IGFBP-1 rs1065780 G allele was 1.204 times as high as that of the A allele,P=0.033.In females and non-smokers,the hypertension incidence risk in the IGFBP-3rs3110697 G allele was 1.234 and 1.189 times as high as that of the A allele,respectively.In females and non-smokers,the hypertension incidence risk in the IGFBP-3 rs2132572 T allele was1.281 and 1.227 times as high as that of the A allele,respectively?all P<0.05?.In the use of antihypertensive drugs patients,the rs3110697 AA genotype carriers'systolic blood pressure?SBP?was?148.82�20.35?mm Hg was significantly higher than that of GG?142.03�16.27?mm Hg and GA?142.89�16.18?mmHg,P=0.021;rs2453839 CC genotype carriers'of SBP?147.24�18.7?mmHg higher than that of TT?141.94�15.87?mmHg and TC?143.39�17.21?mmHg,P=0.042.In the 137 hypertensive patients and 159 healthy controls,the median(P₂₅,P₇₅)of serum IGFBP1 levels in hypertensive patients 16.77?6.97,50.35?ng/ml was significantly lower than that in the control group 32.37?10.12,73.72?ng/ml,P=0.011.Both in the control and hypertension group,carriers of the minor allele of both rs1065780 had higher serum IGFBP-1 levels compared to wild type and homozygous carriers?P<0.001?.While the rs2854843 and rs13223993 minor allele carriers had lower levels of IGFBP-1 compared with the wild type and homozygous carriers?all P<0.05?.Conclusion:These findings suggest that IGFBP-3 rs2132572 TT genotype and rs3110697 AA genotype may be associated with hypertension in Chinese Han population.The risk of smokers individual hypertension is increased by carrying the IGFBP-1rs1874479 G allele.Carrying the IGFBP-1 rs1065780 G allele is a risk factor for hypertension in males.Carrying the IGFBP-3 rs3110697 G allele and rs2132572 T allele are risk factors for hypertension in females and non-smokers.The variation of rs3110697 and rs2453839 might affect the antihypertensive drugs effect.The decrease of serum IGFBP-1 is closely related to hypertension.Serum IGFBP-1 is confirmed to be an informative risk marker for hypertension.