Genetic Modulation on the Relationship of Low Birth Weight to Metabolic Syndrome

描述（由申请人提供）：低出生体重是宫内生长受限的一个指标，已被证明与成人心血管（C-V）疾病、2型糖尿病和代谢综合征相关，包括体脂、胰岛素抵抗、血压和脂蛋白。低出生体重与代谢综合征多个组成部分的相互关系作为一个复杂的实体和潜在的遗传因素可以进一步阐明使用先进的复杂的统计方法，如通径分析。本研究的具体目的是：1)利用通径分析模型，在黑人和白人个体中，按生长期纵向和横断面分析低出生体重对代谢综合征组成部分的影响；2)研究相关候选基因对低出生体重对儿童至成年期代谢综合征组成部分纵向趋势关系的修饰作用。这些特定目标将使用Bogalusa心脏研究中现有的表型和候选基因型数据进行检查，Bogalusa心脏研究是一项长期的基于社区的双种族（65%白人，35%黑人）研究，从1973年开始，从儿童开始研究C-V疾病的自然史。研究队列I按生长期进行横断面分析，包括6,051名具有国家出生证明信息和代谢综合征成分的个体；纵向分析的队列II由2,775名个体组成，这些个体在1973-2008年期间具有出生体重和代谢综合征成分的连续测量数据，在儿童期和成年期各测量至少2次，共有16,276项观察结果；用于遗传分析的队列III （n= 1447, 990名白人，457名黑人）是队列II的一个子集，具有候选基因型数据。21个与出生体重和代谢综合征相关的候选基因的单核苷酸多态性（SNPs, n=618）将作为个体snp、单倍型和基因-基因相互作用进行分析。将进行横断面和纵向通径分析，通过单倍型组检查出生体重与代谢综合征成分的关系。候选基因的调节作用将根据单倍型组间通径分析参数的显著差异进行测试。本研究确定的基因位点将为进一步研究多基因的多效性和加性效应提供基础，并为低出生体重和代谢综合征变量极值受试者的重要候选基因进行更密集的测序提供基础。这对改善产前护理和制定早期预防成人丙型肝炎的策略具有重要意义。

DESCRIPTION (provided by applicant): Low birth weight, an indicator of intrauterine growth restriction, has been demonstrated to be associated with adult cardiovascular (C-V) disease, type 2 diabetes and metabolic syndrome components, including body fatness, insulin resistance measures, blood pressure, and lipoproteins. The interrelationship of low birth weight to multiple components of the metabolic syndrome as a complex entity and the underlying genetic factors can be elucidated further using an advanced sophisticated statistical method like path analysis. The Specific Aims of the proposed research are 1) to examine the impact of low birth weight on metabolic syndrome components by using a path analysis model, longitudinally and cross-sectionally by growth periods, in black versus white individuals, and 2) to investigate the modifying effects of relevant candidate genes on the relationship of low birth weight to longitudinal trends of metabolic syndrome components from childhood to adulthood. These specific aims will be examined using existing phenotypes and candidate gene genotype data available in the Bogalusa Heart Study, a long-term biracial (65% white, 35% black) community-based study of the Natural History of C-V Disease beginning in childhood, since 1973. Study Cohort I for cross-sectional analyses by growth periods consists of 6,051 individuals who have State birth certificate information and metabolic syndrome components; Cohort II for longitudinal analyses consists of 2,775 individuals who have data on birth weight and serial measurements of metabolic syndrome components measured at least 2 times each in childhood and in adulthood during 1973-2008, with 16,276 observations; Cohort III (n=1,447, 990 whites, 457 blacks) for genetic analyses is a subset of Cohort II with candidate gene genotype data available. Single nucleotide polymorphisms (SNPs, n=618) in 21 candidate genes related to both birth weight and metabolic syndrome will be analyzed as individual SNPs, haplotypes and gene-gene interactions. Path analyses will be performed cross-sectionally and longitudinally to examine the relationship of birth weight to the metabolic syndrome components by haplotype groups. The modulating effect of the candidate genes will be tested in terms of significant differences in the path analysis parameters between haplotype groups. The genetic loci identified in the proposed research will provide a basis for further research on the pleiotropic effects and additive effects of multigenes, and more dense sequencing in significant candidate genes in subjects who have a low birth weight and extremes values of the metabolic syndrome variables. This has important implications for improving prenatal care and developing strategies beginning early to prevent adult C-V disease. PUBLIC HEALTH RELEVANCE: Low birth weight is an indicator of baby growth restriction before birth, and associated with adult heart disease, diabetes and risk factors such as obesity, high blood pressure, high cholesterol and high blood sugar. The findings from this research has important implications for improving prenatal care and developing strategies beginning early to prevent adult heart disease.