RESUMO
OBJECTIVE: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance. RESULTS: A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance. CONCLUSIONS: Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.
Assuntos
Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/genética , Etnicidade/genética , Proteínas de Homeodomínio , Indígenas Norte-Americanos/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo Genético , Transativadores/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idade de Início , Arizona , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Códon , Dimerização , Éxons , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Fator 3-beta Nuclear de Hepatócito , Fator 4 Nuclear de Hepatócito , Humanos , Mutação , Fatores de Transcrição/químicaRESUMO
Electrophoretic variants of the vitamin D-binding protein (DBP) have been associated with type 2 diabetes as well as with metabolic characteristics that predispose to type 2 diabetes in several populations. The Gc gene that encodes DBP maps to chromosome 4q12, a region that has recently been found to be potentially linked to plasma glucose and insulin concentrations in Pima Indians. Therefore, the gene that encodes DBP was analyzed as a candidate gene for our linkage findings in the Pima Indians. Sequence analysis of the coding exons identified two previously described missense polymorphisms at codons 416 and 420, which are the genetic basis for the three common electrophoretic variants of DBP (Gc1f, Gc1s, and Gc2). These variants in DBP were associated with differences in oral glucose tolerance in nondiabetic Pima Indians.