Objective To investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH i...Objective To investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH in a genetically homogenous Mongolia rural population of China. Methods Individuals (n=1099) were recruited from general population of Kezuohouqi Banner in Inner Mongolian Autonomous Region. Results The association was found between ACE genotype DD plus ID and EH, with an interaction between ACE genotype DD plus ID and cigarette smoking in an additive model. Cigarette smoking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 7.10 to 1.16. Interaction between ACE genotype DD plus ID and alcohol drinking on EH appeared an additive model. Alcohol drinking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 1.66 to 1.09. BMI and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 6.15 to 2.49. Interactions between ACE genotype and WHR on EH showed a multiplicative model. In a short, there was an interaction between ACE gene and cigarette smoking, alcohol drinking and BMI on EH, especially in a low dose-exposure effect Conclusion It is important for individuals who carry ACE D allele gene to prevent EH, and furthermore, to prevent and control coronary heart disease, in a view of population-based prevention.展开更多
Abstract Objective The incidence of hypertension in Tibet ranks highest among all Chinese provinces. This may be due to genetic changes caused by Tibet＇s unique natural environment and agrarian lifestyle, prompting u...Abstract Objective The incidence of hypertension in Tibet ranks highest among all Chinese provinces. This may be due to genetic changes caused by Tibet＇s unique natural environment and agrarian lifestyle, prompting us to investigated the relationship between gene polymorphisms and hypertension. Methods Blood samples were collected from 229 hypertensive participants and 372 healthy （control） participants from five Tibetan counties. Seventeen single nucleotide polymorphisms were investigated for their connection to hypertension. Results The C allele at rs2070744 of the NOS3 gene was shown to be significantly associated with hypertension （P=0.0443; OR=1.636）. Additionally, the T allele of rs4961 of the ADD gene was correlated with hypertension in women （P=0.03124; OR=1.584）. Conclusion In this study we found that the NOS3 and ADD genes were related to a high incidence of hypertension among Tibetans. N053 gene plays a role in regulating vascular tone and blood vessel diameter, which may be altered by the low-oxygen environment of Tibet. ADD is involved in water and salt metabolism, which is consistent with the high-salt diet of Tibetans. The correlations elucidated by our study were different from those of other ethnic groups, indicating that these findings may be specific to the Tibetan people.展开更多
Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously boun...Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.展开更多
Background Transgenic overexpression of human prostasin in rats disturbs salt balance and causes hypertension. We investigated whether genetic variations in prostasin were implicated in hypertension or related phenoty...Background Transgenic overexpression of human prostasin in rats disturbs salt balance and causes hypertension. We investigated whether genetic variations in prostasin were implicated in hypertension or related phenotypes in the Xinjiang Kazakh population.Methods We sequenced all exons and the promoter regions of the prostasin gene in 94 hypertensive individuals, and the genotype identification was performed by the TaqMan polymerase chain reaction method. Case-control studies were conducted in 938 Kazakh subjects.Results E342K and 2827G＞A, which are novel variants, were successfully genotyped in the general Xinjiang Kazakh population with a sample size of 938 individuals （406 men and 532 women）. Only one hypertensive patient was identified with the E342K mutation. No significant association was observed between 2827G＞A and hypertension. However,quantitative traits of hypertensive intermediate phenotypes were significantly associated with the A allele; P=-0.041 and 0.034 for body mass index （BMI） in the additive and recessive models, P=0.042 and 0.018 for OGTT-2h glucose in the additive and recessive models, P=0.031 for IRT-3h insulin in the recessive model, and P=0.038 for serum potassium in the dominant model.Conclusions This study does not provide evidence of a major role of prostasin variation in blood pressure modulation.However, association of prostasin polymorphisms with hypertension and metabolic effects can be observed in our population. Further investigation is warranted to clarify the relevance of prostasin polymorphisms to blood pressure regulation.展开更多
基金This study was supported by Beijing Municipal Natural Sciences Foundation (Grant No. 7001004) Research Fund for the Doctoral Training Program from the Ministry of Education (Grant No. 20020023009) China Medical Board in New York (Grant No. 96-657).
文摘Objective To investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH in a genetically homogenous Mongolia rural population of China. Methods Individuals (n=1099) were recruited from general population of Kezuohouqi Banner in Inner Mongolian Autonomous Region. Results The association was found between ACE genotype DD plus ID and EH, with an interaction between ACE genotype DD plus ID and cigarette smoking in an additive model. Cigarette smoking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 7.10 to 1.16. Interaction between ACE genotype DD plus ID and alcohol drinking on EH appeared an additive model. Alcohol drinking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 1.66 to 1.09. BMI and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 6.15 to 2.49. Interactions between ACE genotype and WHR on EH showed a multiplicative model. In a short, there was an interaction between ACE gene and cigarette smoking, alcohol drinking and BMI on EH, especially in a low dose-exposure effect Conclusion It is important for individuals who carry ACE D allele gene to prevent EH, and furthermore, to prevent and control coronary heart disease, in a view of population-based prevention.
基金supported by grants from the Chinese Ministry of Science and Technology(973Program,Grants#2006CB504103)Chinese Academy of Sciences(#KSCX2-YW-R-76)Science and Technology Plan of the Tibet Autonomous Region(#2007-2-18)
文摘Abstract Objective The incidence of hypertension in Tibet ranks highest among all Chinese provinces. This may be due to genetic changes caused by Tibet＇s unique natural environment and agrarian lifestyle, prompting us to investigated the relationship between gene polymorphisms and hypertension. Methods Blood samples were collected from 229 hypertensive participants and 372 healthy （control） participants from five Tibetan counties. Seventeen single nucleotide polymorphisms were investigated for their connection to hypertension. Results The C allele at rs2070744 of the NOS3 gene was shown to be significantly associated with hypertension （P=0.0443; OR=1.636）. Additionally, the T allele of rs4961 of the ADD gene was correlated with hypertension in women （P=0.03124; OR=1.584）. Conclusion In this study we found that the NOS3 and ADD genes were related to a high incidence of hypertension among Tibetans. N053 gene plays a role in regulating vascular tone and blood vessel diameter, which may be altered by the low-oxygen environment of Tibet. ADD is involved in water and salt metabolism, which is consistent with the high-salt diet of Tibetans. The correlations elucidated by our study were different from those of other ethnic groups, indicating that these findings may be specific to the Tibetan people.
基金National Center for Research Resources,Grant/Award Number:RR020128NHGRI,National Institute of General Medical Sciences,Grant/Award Numbers:1R01GM120156-01A1,K23GM147805,R35GM131812,T32GM008425+3 种基金NHLBI,NINDS,NCI,Grant/Award Number:1R03CA223906-01NIDA,NIMH,Office of the Director of the National Institutes of Health,Indiana University School of Medicine,Grant/Award Number:NIH/NCRRRR020128NIH-NIGMS,Grant/Award Numbers:t32gm008425,r35gm131812,1r01gm120156-01a1,k23gm147805NIH-NCI,Grant/Award Number:1R03CA223906-01。
文摘Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
文摘Background Transgenic overexpression of human prostasin in rats disturbs salt balance and causes hypertension. We investigated whether genetic variations in prostasin were implicated in hypertension or related phenotypes in the Xinjiang Kazakh population.Methods We sequenced all exons and the promoter regions of the prostasin gene in 94 hypertensive individuals, and the genotype identification was performed by the TaqMan polymerase chain reaction method. Case-control studies were conducted in 938 Kazakh subjects.Results E342K and 2827G＞A, which are novel variants, were successfully genotyped in the general Xinjiang Kazakh population with a sample size of 938 individuals （406 men and 532 women）. Only one hypertensive patient was identified with the E342K mutation. No significant association was observed between 2827G＞A and hypertension. However,quantitative traits of hypertensive intermediate phenotypes were significantly associated with the A allele; P=-0.041 and 0.034 for body mass index （BMI） in the additive and recessive models, P=0.042 and 0.018 for OGTT-2h glucose in the additive and recessive models, P=0.031 for IRT-3h insulin in the recessive model, and P=0.038 for serum potassium in the dominant model.Conclusions This study does not provide evidence of a major role of prostasin variation in blood pressure modulation.However, association of prostasin polymorphisms with hypertension and metabolic effects can be observed in our population. Further investigation is warranted to clarify the relevance of prostasin polymorphisms to blood pressure regulation.
