Linkage analysis of GLUT1 (HepG2) and GLUT2 (liver/islet) genes in familial NIDDM.
Familial NIDDM probably results from combined inherited defects of insulin secretion and action. Members of the facilitative glucose transporter family are strong candidates for both defects, and RFLPs for both GLUT1 (erythrocyte) and GLUT2 (liver/islet) genes have been associated with NIDDM in some populations. To test the hypothesis that GLUT1 and GLUT2 mutations contribute to the inherited predisposition to NIDDM, we examined linkage of these loci with NIDDM in 18 large Utah white pedigrees (two and three generation) ascertained for > or = 2 NIDDM siblings. We used two RFLPs detected with Xba1 and Stu1 for the GLUT1 transporter. For the GLUT2 (liver/beta-cell) transporter gene, we used an RFLP detected with EcoR1 and a highly polymorphic (6-allele) dinucleotide (microsatellite) repeat. Analysis was performed with the MLINK program of the LINKAGE package. We tested four models for each locus: dominant and recessive, with IGT alternately considered as unknown affection status, or affected if IGT was diagnosed < or = 45 yr of age and unknown if > 45 yr. Disease gene frequencies were chosen to give approximate disease prevalence in American whites (q = 0.03, dominant; q = 0.25, recessive). Linkage of GLUT1 and NIDDM was strongly and significantly rejected under all models, with total (pooled) LOD scores of -5.7 to -8.9, indicating > 500,000:1 odds against linkage. Pooled LOD scores were significantly negative (< -2.0, or 100:1 odds against linkage) to a recombination fraction of > 5%. No heterogeneity was apparent. Analysis of GLUT2 gave similar results, with LOD scores of < -4.0 under each model, indicating at least 10,000:1 odds against linkage.(ABSTRACT TRUNCATED AT 250 WORDS)
Elbein
S C
SC
Department of Internal Medicine, Veterans Affairs Medical Center, Salt Lake City, Utah 84148.
Hoffman
M D
MD
Matsutani
A
A
Permutt
M A
MA
D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D015252:Deoxyribonucleases, Type II Site-Specific; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008126:Lod Score; D008214:Lymphocytes / Q000502:physiology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D005810:Multigene Family; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D012150:Polymorphism, Restriction Fragment Length
D009004:Monosaccharide Transport Proteins; D009838:Oligodeoxyribonucleotides; D004247:DNA; C025580:endodeoxyribonuclease XBAI; C028868:AGGCCT-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific