Genotypes, Haplotypes, and Blood Pressure Change from Childhood to Adulthood

从童年到成年的基因型、单倍型和血压变化

• 批准号: 7932874
• 负责人: DAVID MICHAEL HALLMAN
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932874
• 关键词: 14 year old; 18 year old; Adolescence; Adolescent; Adult; Affect; African American; Age; Age-Years; Alleles; Blood Pressure; Candidate Disease Gene; Child; Childhood; Chromosomes; Cohort Studies; Communities; Complement; Consent; DNA; Data; Development; Enrollment; Gene Mutation; Genes; Genetic; Genetic Variation; Genotype; Haplotypes; Heart; Human; Hypertension; Individual; Knowledge; Lipids; Longevity; Measurement; Measures; Methods; Mutation; Obesity; Pathology; Pattern; Phenotype; Play; Population; Preventive; Research; Resources; Risk; Risk Factors; Role; Sampling; Serum; Single Nucleotide Polymorphism; Study Subject; Testing; Texas; Time; United States; Variant; age related; base; blood pressure regulation; cardiovascular disorder risk; cohort; critical period; follow-up; genetic analysis; medical examination; public health relevance; trait

DESCRIPTION (provided by applicant): Hypertension affects nearly one-third of adults over age 20 in the United States. While hypertension is found in <10% in adults 20 - 34 years of age, it develops over a period of years, and blood pressure levels in children and adolescents are correlated with levels in adults. It is clear that genes play a significant role in regulating blood pressure, but little is known about the effects of genetic variation on the blood pressure changes that occur with age. Identifying the genes and mutations that affect blood pressure change from childhood, through adolescence, and into adulthood is necessary if are to understand the pathology of hypertension and target preventive measures most effectively. The Bogalusa Heart Study (BHS), which began as a study of cardiovascular disease (CVD) risk factors in children but evolved to cover the development of CVD risk factors from childhood into adulthood, offers a matchless resource for investigating the genetic factors influencing within-individual changes over time from childhood to adulthood in blood pressure and other CVD risk factors. We propose to investigate 3072 single-nucleotide polymorphisms (SNPs), both individually and as multilocus haplotypes (combinations of SNP alleles on a single chromosome), in 115 genes known or strongly suspected to affect blood pressure and risk of hypertension, using 1735 BHS subjects who consented to participate in studies of the genetics of CVD risk factors. Of these, 1687 (97.2%) were examined at least twice. The sample includes 1195 whites (with 5927 examinations) and 540 African Americans (with 2677 examinations); subjects were from 3 - 38 years of age when examined. Multilevel regression will be used to measure the effect of individual SNPs on longitudinal blood pressure profiles and identify those that affect age-related changes in blood pressure. In genes in which individual SNPs show significant associations, follow-up multilocus analyses will use evolutionary relationships among haplotypes to determine appropriate sets of haplotype comparisons to identify specific haplotypes associated with blood pressure changes over time and aid in locating functional mutations while reducing the number of necessary tests and increasing statistical power. All SNPs and haplotypes showing positive associations in the BHS cohort will be genotyped and analyzed in a replication sample of 506 whites (with 4503 examinations) and 136 African Americans (with 1007 examinations) drawn from Project HeartBeat!, a study of CVD risk factors in which schoolchildren from two Texas communities were enrolled at 8, 11, or 14 years of age, then received medical examinations 3 times a year for 4 years. The proposed research, involving the only two cohorts for whom extensive longitudinal data exist for biracial populations that include substantial numbers of African Americans, will greatly extend our knowledge of the genetic factors that affect blood pressure over a large portion of the human lifespan. Because many genes that affect blood pressure may also affect traits such as obesity and serum lipid levels, the proposed research will also provide opportunities to investigate genes affecting changes in other CVD risk factors. PUBLIC HEALTH RELEVANCE: Hypertension affects nearly one-third of adults in the United States, and though frank hypertension is uncommon in adults under 34 years of age, blood pressure levels in children and adolescents are correlated with levels in adults. It is clear that genes play a significant role in regulating blood pressure, but little is known about the effects of genes on the blood pressure changes that occur with age. Our proposed study will investigate genes likely to affect blood pressure changes over time in individuals 3-38 years of age, and will greatly extend our knowledge of the genetic factors that affect blood pressure over a large portion of the human lifespan.

描述（由申请人提供）：在美国，近三分之一的 20 岁以上成年人患有高血压。虽然 20 - 34 岁成人中高血压的发病率<10%，但其发展需要数年时间，而且儿童和青少年的血压水平与成人水平相关。很明显，基因在调节血压方面发挥着重要作用，但人们对基因变异对随年龄增长的血压变化的影响知之甚少。如果要了解高血压的病理学并最有效地采取针对性的预防措施，就有必要识别影响从儿童期、青春期到成年期血压变化的基因和突变。 Bogalusa 心脏研究 (BHS) 最初是针对儿童心血管疾病 (CVD) 危险因素的研究，后来发展到涵盖从儿童到成年的 CVD 危险因素的发展，为研究影响体内的遗传因素提供了无与伦比的资源。从童年到成年，个体的血压和其他心血管疾病危险因素随着时间的推移而发生变化。我们建议使用 1735 名 BHS 受试者，研究 115 个已知或强烈怀疑影响血压和高血压风险的基因中的 3072 个单核苷酸多态性 (SNP)，无论是单独的还是作为多位点单倍型（单条染色体上的 SNP 等位基因的组合）同意参加 CVD 危险因素遗传学研究的人。其中，1687 人（97.2%）至少接受过两次检查。样本包括 1195 名白人（进行了 5927 项检查）和 540 名非裔美国人（进行了 2677 项检查）；检查时受试者的年龄为 3 - 38 岁。多级回归将用于测量单个 SNP 对纵向血压曲线的影响，并确定那些影响与年龄相关的血压变化的因素。在单个 SNP 显示显着关联的基因中，后续多位点分析将利用单倍型之间的进化关系来确定适当的单倍型比较组，以识别与血压随时间变化相关的特定单倍型，并帮助定位功能突变，同时减少必要的测试和增加统计功效。 BHS 队列中显示出正相关的所有 SNP 和单倍型都将在由 506 名白人（进行了 4503 次检查）和 136 名非裔美国人（进行了 1007 次检查）组成的重复样本中进行基因分型和分析，该样本来自 HeartBeat! 项目，这是一项针对 CVD 风险因素的研究。来自德克萨斯州两个社区的学童在 8 岁、11 岁或 14 岁入学，然后每年接受 3 次体检4年了。拟议的研究涉及仅有的两个拥有广泛纵向数据的混血人群（其中包括大量非裔美国人）的研究，将极大地扩展我们对影响人类寿命大部分时间血压的遗传因素的认识。由于许多影响血压的基因也可能影响肥胖和血脂水平等特征，因此拟议的研究还将提供研究影响其他心血管疾病危险因素变化的基因的机会。 公共健康相关性：高血压影响着美国近三分之一的成年人，尽管明显的高血压在 34 岁以下的成年人中并不常见，但儿童和青少年的血压水平与成人的水平相关。很明显，基因在调节血压方面发挥着重要作用，但人们对基因对随年龄增长的血压变化的影响知之甚少。我们提出的研究将调查可能影响 3-38 岁个体血压随时间变化的基因，并将极大地扩展我们对影响人类大部分寿命中血压的遗传因素的认识。