MOLECULAR GENETICS OF GESTATIONAL DIABETES MELLITUS--A GENETIC PREDISPOSITION

妊娠期糖尿病（GDM）妇女在妊娠期外发展为糖尿病的比率为每年0.5%，因此，在诊断时平均年龄相对较年轻的非胰岛素依赖型糖尿病（NIDDM）患者中占相当大的比例。此外，b细胞功能受损是GDM女性发生DM风险的重要早期预测指标。基于这些原因，我们假设患有妊娠期糖尿病（GDM）的女性与其他NIDDM的表现不同，具有一组独特的遗传特征。拟议的研究旨在从几组参与者中创建基因组DNA库和表型信息，包括(i)有GDM病史的NIDDM女性，（ii）有GDM病史但糖耐量正常的女性，（iii）没有GDM病史的女性，（iv）典型的晚发性NIDDM个体（定义为50岁以后发病）。(v)葡萄糖耐量正常但有NIDDM家族史、年龄超过50岁或种族（非裔美国人、西班牙裔或美洲原住民）的迟发性NIDDM危险因素的参照组。这些DNA和表型信息将在当前和未来的研究中用于解决我们的假设，通过检查先前确定的基因多态性/突变的频率，这些基因在不同的参与者群体中易患年轻人的成熟型糖尿病（MODY）、NIDDM和肥胖（NIDDM的一个危险因素），以及这些多态性/突变与不同表型特征改变的关联。这些研究将使用约1000人进行口服葡萄糖耐量试验，以确定他们是否有资格参加西北大学医学院的糖尿病预防项目，约450人将参加另一项crc批准的研究（“瘦素受体基因的多态性变异与肥胖和妊娠糖尿病相关”- 597协议）。在拟议的研究中进行的具体分析将是确定与其他四组相比，有GDM病史的NIDDM女性中转录因子肝细胞核因子-1a的突变率。该基因的突变导致年轻人的成熟型糖尿病（MODY），因此与年轻时的糖尿病发病有关。

Women who develop gestational diabetes mellitus (GDM) progress to diabetes outside of pregnancy at a rate >5%/yr and account, therefore, for a sizable proportion of people with non-insulin dependent diabetes mellitus (NIDDM) whose mean age at diagnosis is relatively young. Moreover, impaired b-cell function is an important early predictor of the risk of developing DM among women with GDM. For these reasons, we have hypothesized that women with gestational diabetes mellitus (GDM) share a unique set of genetic characteristics apart from other presentations of NIDDM. The proposed studies are designed to create a bank of genomic DNA from and phenotypic information on several groups of participants, including (i)women with NIDDM subsequent to a history of GDM, (ii)women with a history of GDM who have normal glucose tolerance, (iii)women who do not have a history of GDM, (iv)individuals with typical, late-onset NIDDM (defined as onset after age 50), and (v)a reference group of individuals with normal glucose tolerance but who are at risk factor for late-onset NIDDM based upon a family history of a first degree relative with NIDDM, age over 50, or ethnicity (African-American, Hispanic, or Native American). This DNA and phenotypic information will be used to address our hypothesis in the present and future studies by examining the frequency of polymorphisms/mutations in previously identified genes that predispose to the development of maturity onset diabetes of the young (MODY), NIDDM, and obesity (a risk factor for NIDDM) in the different groups of participants and the association of those polymorphisms/mutations with alterations in the different phenotypic characteristics. These studies will be conducted using the about 1000 people who are currently undergoing oral glucose tolerance tests to determine their eligibility for participation in the Diabetes Prevention Program at Northwestern University Medical School and about 450 people who will be enrolled in another CRC-approved study ("Are Polymorphic Variants of the Leptin Receptor Gene Associated with Obesity and Gestational Diabetes Mellitus" - Protocol 597). The specific analysis that will be conducted in the proposed study will be to determine the prevalence rate of mutations in the transcription factor hepatocyte nuclear factor-1a in women with NIDDM subsequent to a history of GDM compared to the other four groups. Mutations in this gene result in maturity-onset diabetes of the young (MODY) and are, thus, associated with onset of diabetes at a young age.