Study On The Early Warning Effect Of Adipose Factor Profile And Related Genes On Early-onset Hypertensio

[Background]Hypertension has become a worldwide public health problem.The Chinese are facing the double pressure of the prevalence of population ageing and metabolic risk factors,and the prevalence of hypertension is increasing.With the rapid development of social economy and the change of life style and nutrition supplement,the incidence of hypertension tends to be younger.The prevalence of early-onset hypertension is increasing in China.Early-onset hypertension has a trajectory effect,which can lead to refractory hypertension,target organ damage,heart disease,stroke and other major health problems,resulting in a heavy economic and social burden.Therefore,it is very important to explore the biomarkers related to early-onset hypertension for early recognition and intervention of early-onset hypertension.Early-onset hypertension is a complex disease caused by both genetic and environmental factors.Obesity is a major risk factor for hypertension,which can be caused by a variety of mechanisms including sympathetic nervous system activation,inflammation and insulin resistance.Adipose tissue is an endocrine organ.It can secrete many kinds of fat factors,such as leptin and adiponectin.These fat factors are related to inflammation and insulin resistance,it may play a key role in the occurrence and development of early-onset hypertension.However,whether changes in adipokine secretion patterns are associated with the risk of hypertension in children and adolescents remains unclear in the Chinese population.Moreover,there is little epidemiological evidence that changes in adipokine secretion patterns in childhood affect the risk of new hypertension in adults.At the same time,whether these adipokines are mediating factors associated with obesity and early hypertension has not been clarified.In addition,the recent European genome-wide Association Study(GWAS)found that many of the SNPS related to blood pressure were associated with obesity,so the function of adipose tissue plays an important role in the development of blood pressure.Adipokine is a biomarker of adipose tissue function and adipokine related genes play an important role in the study of hypertension.However,there have been limited reports on the association of adipokine related genes with early onset hypertension.Therefore,this study will be based on a large prospective cohort of Beijing children and adolescents with metabolic syndrome(BCAMS),starting with adipokines that reflect fat function,to investigate the relationship between the levels of plasma leptin,adiponectin and Retinol binding protein 4(RBP4)and the development of early-onset hypertension,combined with the follow-up data,we explored the role of childhood adipokines in the early prediction of adult-onset hypertension,and elucidated the mediating role of adipokines in the obesity-hypertension association.In addition,this study will primarily explore the genetic variation of adipokines associated with early-onset hypertension,in order to provide new ideas for the mechanism,accurate identification and early prevention and control of early-onset hypertension.[Methods]Participants were from the Beijing Child and Adolescent Metabolic Syndrome Study(BCAMS)cohort,which was launched in 2004.In the 2004 BCAMS cohort,3510 children and adolescents aged 6-18 years were recruited and followed up for 10 years,with a total of 987 individuals obtaining follow-up data on basic volume measures and 667 participants completing in-depth follow-up.The information of living habits,socioeconomic factors and family history of hypertension at baseline and follow-up were investigated by questionnaire,body mass index such as height,weight,waist circumference and Body fat percentage were measured.Hypertension was measured and screened according to the Chinese guidelines for the prevention and treatment of hypertension(2018).Insulin levels were measured by enzyme-linked immunosorbent assays,and serum levels of the adipokines leptin,adiponectin,and RBP4 were followed up.Genome-wide Association Studies(GWAS)were used to identify six gene loci with high adiponectin level.Based on baseline and follow-up population,multivariate regression analysis was used to explore the independent and co-effects of adipokines on early-onset hypertension To explore the role of adipokines in the relationship between obesity and hypertension by mediation analysis.[Results]1.The association analysis of adipokines and their genes with hypertension in children and adolescentsThe baseline cross-sectional analysis of 987 children and adolescents showed that compared with children and adolescents with normal blood pressure,the serum levels of leptin and RBP4 were increased and the serum levels of adiponectin were decreased in children with hypertension(p<0.05).After adjusting for age,sex,puberty,exercise,diet score,and family history of hypertension,leptin,high molecular adiponectin,and RBP4 were associated with systolic and diastolic blood pressure in children and adolescents(all P<0.05),increased levels of leptin and RBP4 and decreased levels of high molecular adiponectin were associated with high normal blood pressure and increased risk of hypertension in children and adolescents(p<0.05 for both).However,the Association of leptin and adiponectin with blood pressure in children and adolescents was not independent of BMI.After further adjustment for BMI,only RBP4 levels independently predicted systolic(β=1.18,P=0.003)and diastolic(β=0.97,P=0.002)blood pressure.This suggests that the imbalance of adipokines is an early sign of elevated blood pressure in children and adolescents.The adiponectin-related ADIPOQ rs6773957 locus had a protective effect on normal high blood pressure in children and adolescents(or=0.800.95%CI:0.641-0.998,P<0.05),the CDH13 RS4783244 locus showed a protective effect on hypertension in children and adolescents(or=0.766,95%CI:0.589-0.997,P<0.05).These results suggest that adiponectin and fat function play an important role in maintaining blood pressure homeostasis.2.The predictive value of childhood adipokines for new-onset hypertension after 10 years of follow-upLongitudinal data show that,for children and adolescents with normal baseline blood pressure,after 10 years of follow-up,the new-onset hypertension group had higher baseline leptin levels and lower levels of macromolecular adiponectin,suggesting that leptin-adiponectin imbalance may play an important role in the development of new-onset hypertension.Leptin and high-molecular-weight adiponectin levels during childhood and adolescence were associated with systolic and diastolic blood pressure after 10 years of follow-up,but this association was not independent of BMI.After further adjusting for BMI,the association was significantly attenuated,or even no longer significant.However,after adjusting for confounders,including BMI,baseline leptin to macromolecular adiponectin ratio(L/A)remained significantly associated with increased systolic blood pressure(β=10.58,p<0.001)and diastolic blood pressure(β=6.33,p=0.001)after 10 years of follow-up.This suggests that L/A may be a potential biomarker that predicts blood pressure better than leptin or adiponectin alone in young people.Furthermore,the present study found a mediating effect of leptin and macromolecular adiponectin between baseline BMI and follow-up systolic and diastolic blood pressure,and this mediating relationship differed by sex.We found that leptin and high-molecular-weight adiponectin had a sex-specific moderating effect on the relationship between baseline obesity and follow-up blood pressure only in female participants,whereas no moderating effect was seen in male participants.These findings suggest that distinct mechanisms may exist for obesity-related hypertension in women and men,which could help to help overweight and obese children develop sex-specific strategies for hypertension control.[Conclusion]The imbalance of leptin,adiponectin and RBP4 may be the cause of early-onset hypertension,and may be an early warning marker of early-onset hypertension.Hypertension in children and adolescents is usually associated with increased levels of leptin,RBP4,and decreased levels of macromolecular adiponectin.RBP4 is an independent predictor of systolic and diastolic blood pressure in children and adolescents.The ADIPOQ rs6773957 locus associated with adiponectin level had a protective effect on normotensive hypertension in children and adolescents,while the CDH13 RS4783244 locus had a protective effect on hypertension in children and adolescents.These results suggest that adiponectin and fat function play an important role in maintaining blood pressure homeostasis in children and adolescents.Compared with young people without new-onset hypertension,those with new-onset hypertension had higher baseline leptin levels and lower levels of high-molecular-weight adiponectin,but the association of leptin and adiponectin with new-onset hypertension was mainly influenced by BMI.Childhood leptin/adiponectin ratio(L/A)was an independent predictor of blood pressure at 10-year follow-up.This suggests that leptin-adiponectin imbalance may play an important role in the development of new-onset hypertension.Furthermore,leptin and high-molecular-weight adiponectin had mediating effects between baseline BMI and follow-up systolic and diastolic blood pressure,and this mediating relationship was only present in women.This suggests that different mechanisms may exist for obesity-related hypertension in women and men,which could help overweight and obese children develop sex-specific strategies for hypertension control.