Insulin-like Growth Factor-1 And Its Receptor Contribute Genetic Susceptibility To Hypertension

Objective: Insulin-like growth factor 1(IGF-1),as a 70 amino acid peptide hormone and shares 50% homology with insulin,binds its receptor to participate in the processes of metabolic and cardiovascular diseases.Recent evidence suggests it is an important mediator in the pathophysiological response to blood pressure increase.Herein,the main aim of this study is to evaluate whether the variants in the genes encoding IGF-1 and the IGF receptor(IGF-1R)are associated with HT.The results of the study will provide a theoretical basis for screening therapeutic target.Methods: All the subjects aged 35-75 years old were recruited from 2 villages in Yixing city,Jiangsu province by cluster sampling approach.Hypertension subjects were referred to Guidelines for hypertension prevention and control in China(2005 revision),and 2012 hypertension cases and 2210 controls were included in hypertension case control study.From May 2014 to January 2016,subjects were followed up to investigate the incidence of hypertension.The association with HT was further replicated positive association in 3551 adolescent populations.Blood serum IGF-1 and IGF-1R were detected and the correlation with blood pressure and genetic variation were evaluated in a randomized sample including 137 cases s and 159 healthy controls.Ten tagging single nucleotide polymorphisms(tag SNPs)of covered IGF-1 and IGF-1R by linkage disequilibrium(LD)analysis and functional prediction for genotyping.Logistic and Cox regression models were used to evaluate the association of IGF-1,IGF-1R and HT in case-control study and follow-up study respectively.General linear model(GLM)was applied to compare blood pressure levels and plasma IGF-1 and IGF-1R levels between genotypes in cases and controls.The haplotype analysis was performed by HAPSTATA3.0 for evaluating the effect of multiple loci in a haplotype block.Results: Case-control study indicated that two SNPs rs1815009 and rs2654981 in IGF-1R had significant association with HT after after adjusted for covariates including age,gender,TC,TG,LDL-C,HDL-C,GLU,BMI,smoking and drinking,the OR and 95%CI were 0.887(0.811,0.971)and 1.193(1.041,1.405),respectively.When stratified by BMI status,we find an interesting phenomenon that the rs35767 G>A variant of IGF-1 was a protective factor in normal weight group whereas was a dangerous factor in obesity population,the OR and 95%CI were 0.833(0.724,0.958)and 1.345(1.021,1.773),respectively.Stratification analysis observed significant association with HT(P(27)0.05)for rs2229765 in(27)55 years,overweight and non-drinking populations and rs2002880 in overweight and drinking populations.Quantitative trait analysis showed that there were significant differences of BP between the genotypes of rs6218,rs5742612 and rs13379905 in treated population.IGF-1R SNPs rs1815009 and rs2654981 were found in the same haplotype block.Compared to reference haplotype Hap(G-C),the frequency of Hap(A-C)was significantly associated with increased risk of HT after adjusted covariates,OR(95%CI)and P value were 1.19(1.02,1.39)and 0.03.In follow-up study,cox regression analyses showed that rs13379905 at IGF-1R was found to be associated with the increased risk of HT(HR=1.238,P=0.041),after adjusted for age,gender,TC,TG,LDL-C,HDL-C,diabetes,BMI,smoking and drinking.The incidence density of CC,CT and TT carriers is 6654.95,7755.36 and 8566.04(100 thousand years),respectively.Significant association of rs13379905 with incident HT were observed in non-drinking(P=0.009)and family history of HT(P=0.001)populations,HR(95%CI)were 1.357(1.080-1.707),2.1(1.381-3.194),respectively.Significant association with incident HT(P(27)0.05)were observed for rs6219 in subgroups of(27)55 years,obesity and family history of HT groups as well as rs2002880 in obesity population.In adolescents,the association of rs13379905(TT vs.CC+CT)and HT was replicated.Particularly,replication study in adolescent showed rs13379905 was significantly associated with prehypertension(pre-HT)in male and female population and the direction of this genetic effect was opposite of that.Further quantitative trait analysis for the Z-scores of SBP and DBP indicated that the Z-score of SBP(1.04±0.97,1.09 ±1.03,1.89±0.66)had a linear increase with the variation(CC,CT,TT)of rs13379905 in boys and P value was 0.042 after adjusting covariates.The IGF-1 and IGF-1R levels showed no difference between HT and control groups, whereas the IGF-1R concentration in the subjects with GG genotype of rs2002880 were significantly different from GA genotype.Conclusions: We observed that there was a significant association of rs1815009 and rs2654981(recessive model)with HT in case-control study as well as a significant association of rs13379905 with the incident HT in a follow-up population.The rs1815009 and rs13379905 of IGF-1R were examined in an adolescent population and the association of rs13379905 with Pre-HT/HT was further verified.Furthermore,stratified analysis showed that rs35767 and rs6219 of IGF-1 had association with HT in different BMI,age and family history,and suggest BMI,age and family history HT might modulate the genetic effects of IGF-1 on HT.These results jointly indicated that the genetic variations in IGF-1 signal pathway might contribute to the susceptibility of HT.