LINKAGE ANALYSIS OF 19 CANDIDATE REGIONS FOR INSULIN-RESISTANCE IN FAMILIAL NIDDM

As part of an ongoing search for diabetes susceptibility loci, we test ed Linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect direct ly or indirectly the action of insulin. Loci were associated with insu lin resistance, known effects on lipid metabolism, or effects on gluco se metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, i nsulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokin ase, the apolipoprotein B and the apolipoprotein A(2) cluster, lipopro tein lipase, hepatic triglyceride lipase, the very-low-density-lipopro tein 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 chromos ome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha. gene and the Friedreich's ataxia region. AU reg ions 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 loc us under parametric models (logarithm of odds [LOD] <-2) and nonparame tric analyses, except growth hormone (LOD 1.42; P < 0.005, nonparametr ic 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. A dditionally, 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 ho rmone locus on chromosome 17 warrants further analysis in other popula tions.