RESUMO
Considerable data support a genetic basis to susceptibility for NIDDM, but previous analysis of candidate genes has failed to identify a major susceptibility locus. Among regions with multiple potential candidates is chromosome 11, which includes the apolipoprotein C3 cluster, muscle glycogen phosphorylase, two insulin-dependent diabetes loci, the sulfonylurea receptor, and ataxia telangiectasia. To test linkage, we initially typed 19 markers at 10- to 15-cM intervals along chromosome 11. Analyses carried out under parametric models in members of 16-19 families of northern European ancestry detected possible linkage of NIDDM to D11S916. Nonparametric methods detected possible linkage to NIDDM at D11S901, which was 5- 10 cM distant, and at D11S935, which was approximately 30 cM distant. Both D11S916 and D11S901 were near the IDDM4 locus. To further test linkage, we typed five additional markers within 5 cM of D11S916 in the initial 19 families. We also tested markers from the linked region in a second set of recently sampled additional families. Two additional markers (D11S527 and D11S534) showed possible linkage in the initial 19 families, but none of the markers were linked to NIDDM in a separate set of families from the same ethnic background. The best evidence for linkage in the combined data set of the initial 19 families and 26 additional families was at D11S534 under parametric analysis (Z = 1.20) and at D11S935 under nonparametric analysis (affected pedigree number, P = 0.0013). Our findings suggest marginal evidence for a diabetes susceptibility locus in the region between D11S901 and D11S935, with the best evidence for a locus at or near D11S935. Replication of these findings in other populations will be necessary to distinguish false-positive linkage from a true NIDDM susceptibility locus.
Assuntos
Cromossomos Humanos Par 11 , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Repetições de Microssatélites , Adulto , Idoso , Mapeamento Cromossômico , Europa (Continente)/etnologia , Humanos , Escore Lod , Pessoa de Meia-Idade , UtahRESUMO
As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cromossomos Humanos , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Resistência à Insulina/genética , Adulto , Fatores Etários , Idoso , Apolipoproteína A-II/genética , Sequência de Bases , Mapeamento Cromossômico , Primers do DNA , Diabetes Mellitus/genética , Enzimas/genética , Genes Dominantes , Genes Recessivos , Triagem de Portadores Genéticos , Hormônio do Crescimento/genética , Humanos , Proteínas Substratos do Receptor de Insulina , Escore Lod , Pessoa de Meia-Idade , Dados de Sequência Molecular , Obesidade , Fosfoproteínas/genética , Proteínas/genética , População Branca/genéticaRESUMO
Non-insulin-dependent diabetes mellitus (NIDDM) has been viewed as genetically and physiologically distinct from insulin-dependent diabetes mellitus (IDDM), yet many of the recently suggested IDDM susceptibility loci are likely to increase the risk of diabetes through nonautoimmune mechanisms. To test the hypothesis that the IDDM susceptibility loci include important NIDDM susceptibility loci, we tested the linkage of 14 putative susceptibility regions with NIDDM among families and sibling pairs of Northern European descent. All regions were tested with highly informative microsatellite (simple tandem repeat) polymorphisms in up to 166 affected individuals from 42 families using both parametric and nonparametric methods (149 pairs for sibling pair analyses). We found no evidence for linkage to the majority of loci, including loci that appeared to be linked to IDDM in more than one study. We report some evidence for shared susceptibility for regions on chromosomes 1, 2, and 6. The best evidence based on multilocus affected pedigree member (APM) analysis of markers near D1S191 suggested linkage at P value .0001. This region has not yet been confirmed as an IDDM locus, and our analyses could represent a false-positive result. The role of these three regions will only be clarified by testing in additional families. In combination with other investigations in our laboratory for chromosome 11 susceptibility regions, our data generally do not provide convincing evidence that IDDM and NIDDM share common genetic factors among families of Northern European descent with ascertainment of two or more NIDDM siblings.