Genetics of Birth Weight in Mexican Americans

大量流行病学研究表明，低出生体重与成人生活中的疾病有关，包括2型糖尿病、肥胖症、心血管疾病和代谢综合征。如果是这样的话，试图了解它的病因以及它与成年后疾病之间的联系模式将是至关重要的，特别是在墨西哥裔美国人这样的人群中，他们容易患肥胖症、2型糖尿病和新陈代谢综合症等疾病。关于出生体重变异的遗传基础的知识非常有限。此外，关于出生体重与成人生活中的疾病之间是否有任何共同的遗传决定因素，人们知之甚少。这个项目的目的是进行一项遗传流行病学调查，涉及分子遗传学数据、出生体重数据及其相关的成人表型数据，以及统计基因技术，以检查210个墨西哥裔美国家庭出生体重变异的遗传基础，这些家庭目前正在接受与肥胖、2型糖尿病和高血压等各种疾病的遗传决定有关的调查。具体地说，利用方差成分连锁技术，这项研究的目的是定位新生儿体重的易感基因。我们建议的主要目标是：1)在我们已经收集的602个人的出生体重数据之外，收集大约700个人的出生体重数据；2)使用多点连锁方法来确定潜在的出生体重易感基因座；3)通过在每个感兴趣的区域中键入更多的标记并使用多点连锁分析来进一步探索感兴趣的区域；4)检查这些易感基因座是否对成人疾病和代谢紊乱具有多效性影响；以及5)识别影响出生体重的多个基因座并研究影响出生体重的基因的交互作用。我们将利用拥有10 cM基因组扫描图谱的约800个个体(110个家庭)的出生体重数据，进行多点连锁分析，以确定出生体重的易感基因。在检测到潜在的连锁信号后，我们将使用来自大约1300个个体的数据，在每个区域使用10个标记进行额外的基因分型，以使用多点方法精确定位新生儿体重的易感基因。我们还将研究出生体重的基因座是否对成年后的疾病有任何共同的遗传影响(即多发性)，如肥胖、2型疾病、高血压和新陈代谢综合征。鉴于我们已经在基因组中定位了影响2型糖尿病、肥胖症、胰岛素抵抗和血脂等特征的多个基因位点，本研究将提供一个独特的机会来识别对成年后出生体重和代谢性疾病具有共同遗传影响的基因。

Numerous epidemiological studies have shown that low birth weight is associated with diseases in adult life including type 2 diabetes, obesity, cardiovascular disease and the Metabolic Syndrome. If so, attempts to understand its etiology as well as the patterns underlying its association with diseases in adulthood would be of utmost importance especially in populations such as the Mexican Americans, which are prone to diseases such as obesity, type 2 diabetes and the Metabolic Syndrome. Knowledge about the genetic basis of variation in birth weight is very limited. Also, little is known about whether associations between birth weight and diseases in adult life have any common genetic determinants. The purpose of this project is to conduct a genetic epidemiologic investigation involving molecular genetic data, birth weight data and its related adult phenotypic data, and statistical genetic techniques to examine the genetic basis of variation in birth weight in 210 Mexican American families that are currently under investigation in relation to the genetic determination of various diseases including obesity, type 2 diabetes, and hypertension. Specifically, using variance-components linkage techniques, this study aims to map susceptibility genes for birth weight. The main objectives of our proposal are: 1) to collect birth weight data for about 700 individuals in addition to the birth weight data we have already collected for 602 individuals; 2) to identify potential susceptibility loci for birth weight using multipoint linkage approach; 3) to further explore the regions of interest by typing additional markers in each region of interest and using multipoint linkage analysis; 4) to examine whether these susceptibility loci have any pleiotropic influences on adult diseases and metabolic disorders; and 5) to identify multiple loci affecting birth weight and to examine interactional effects of genes influencing birth weight. Using birth weight data from about 800 individuals (110 families) on whom a 10cM genome scan map is available, we will conduct a multi-point linkage analysis to identify susceptibility loci for birth weight. After detecting potential signals for linkage, we will perform additional genotyping with 10 markers per region using data from about 1300 individuals to precisely localize the susceptibility genes for birth weight using the multipoint approach. We will also examine whether the loci for birth weight have any common genetic influences(i.e., pleitropy) on diseases in adulthood such as obesity, type 2 diseases, hypertension, and the Metabolic Syndrome. Given that we have already localized various loci across the genome affecting such traits as type 2 diabetes, obesity, insulin resistance, and lipids, this present study will provide a unique opportunity to identify genes that have common genetic influences on birth weight and metabolic diseases in adulthood.