HUMAN GLUCAGON-LIKE PEPTIDE-1 RECEPTOR GENE IN NIDDM - IDENTIFICATIONAND USE OF SIMPLE SEQUENCE REPEAT POLYMORPHISMS IN GENETIC-ANALYSIS

Glucagon-Like polypeptides, GLP-1-(7-36)-amide and GLP-1-(7-37), are i mportant regulators of insulin synthesis and secretion by islet beta-c ells. The hypothesis to be tested in this study was that defects in th e islet beta-cell GLP-1 receptor gene contribute to the impaired gluco se-regulated insulin secretion of non-insulin-dependent diabetes melli tus (NIDDM). Human islet GLP-1 receptor genomic clones were isolated, and two highly polymorphic simple sequence repeat regions (GLP-1R-CA1 and GLP-1R-CA3) were identified. Polymerase chain reaction assays were developed to define alleles. For GLP-1R-CA1, 14 alleles were observed in African-Americans (heterozygosity [het] = 0.78) and 6 alleles in C aucasians (het = 0.67). For GLP-1R-CA3, 16 alleles were observed in Af rican Americans (het = 0.89) and 8 alleles in Caucasians (het = 0.83). By genotyping all members of the 40 reference Centre d'Etude du Polym orphisme Humain pedigrees at GLP-1R-CA3, the human GLP-1 receptor gene was uniquely placed on chromosome 6p between GLO1 and D6S19, 20.4 cM from human leukocyte antigen. To assess the possible role of the GLP-1 receptor gene in determining the genetic susceptibility to NIDDM, all elic frequencies of GLP-1R-CA1 and GLP-1R-CA3 were compared between Af rican-American NIDDM patients (n 95) and control subjects (n = 93). Th e frequencies did not differ between the two groups at either GLP-1R-C A1 or GLP-1R-CA3. The GLP-1 receptor gene simple-sequence repeat polym orphisms were used for linkage analysis in Utah Mormon pedigrees (n = 16) with NIDDM. Linkage could be rejected (logarithm of odds scores < -2.0) under both dominant and recessive models to distances in excess of 5 cM. Thus, we concluded that inherited defects in the GLP-1 recept or are not a major risk factor for NIDDM in these two racial groups.