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–α 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. On initial analysis, each region was rejected as a major diabetogenic locus under parametric models (logarithm of odds [LOD] <− 2) and nonparametric analyses, except growth hormone (LOD = 1.42; P < 0.005, nonparametric analysis) and IRS1 (P < 0.001, nonparametric analysis). Linkage of IRS1 and NIDDM was no longer significant when additional families were tested, and linkage of growth hormone under parametric analysis could likewise be rejected. However, under nonparametric, model-independent analysis, linkage to the growth hormone region remained suggestive. Additionally, possible evidence for linkage (P < 0.05) was found under nonparametric models for apolipoprotein A2 in an expanded sample of 29 families. We excluded multiple candidates as major diabetogenic loci, including fatty acid binding protein 2, IRS1, the insulin-responsive glucose transporter, and rad. However, the region around the growth hormone locus on chromosome 17 warrants further analysis in other populations.

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