MOLECULAR GENETICS OF GESTATIONAL DIABETES MELLITUS--A GENETIC PREDISPOSITION

Northwestern University, Evanston IL

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Abstract

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.