Program Nr: 196

Quantitative trait loci (QTL) genome scan in two independent sets of Finnish affected sibling pair families with type 2 diabetes. L.J. Scott1, R.M. Watanabe2, K. Silander3, K.L. Mohlke3, H.M. Stringham1, C. Li1, K. Doheny4, E. Pugh4, T.T. Valle5, R.N. Bergman6, J. Tuomilehto5, F. Collins2, M. Boehnke1. 1) Dept Biostat, Univ Michigan, Ann Arbor, MI; 2) Dept Prevent Med, Keck Sch Med, Univ S California, Los Angeles, CA; 3) NHGRI, NIH, Bethesda, MD; 4) CIDR, Johns Hopkins Univ, Baltimore, MD; 5) Dept Epidemiol Hlth Promotion, Nat Pub Hlth Inst, Helsinki, Finland; 6) Dept Physiol Biophys, Keck Sch Med, Univ S California, Los Angeles, CA.
   The goal of the Finland-U.S. Investigation of NIDDM Genetics (FUSION) is to identify genes that predispose to type 2 diabetes and/or influence diabetes related quantitative traits. In a previous genome scan of 580 families (F1), we examined QTL for insulin, glucose, and obesity related traits using variance components on affected individuals. We subsequently collected a second set of 269 families (F2), on which 477 microsatellite markers were typed. The F1 and F2 probands had similar characteristics but the F2 group tended to be milder diabetics. The highest maximum lod score (MLS) in the combined F1+F2 groups was 4.1 for C-peptide (CP) based empirical insulin secretion (IRC=CP/glucose) at 56.5 cM from the p-ter on chromosome 3 (Chr 3). Specifically, for F1, F2 and F1+F2, IRC had MLSs of 3.6, 1.2, and 4.1 (64.0, 56.5, 56.5 cM) and C-peptide had MLSs of 2.7, 1.5 and 3.5 (63.5, 56.5, 56.5 cM). On Chr 7, for F1, F2 and F1+F2, fasting glucose had MLSs of 1.7, 1.1 and 2.7 (80.0, 66.0, 79.0 cM) and IRC had MLSs of 2.3, 1.5 and 2.4 (76.5, 54.0, 71.0 cM). In addition to traits included in the original F1 QTL genome scan, we examined lipid and blood pressure variables in both F1 and F2. On Chr 7, triglyceride (TG), HDL ratio (HDL/total cholesterol) and cholesterol had MLSs in F1 of 1.4, 3.5, and 2.3 (135.5, 142.0, 142.5 cM), respectively (no signals in F2). On Chr 20 the MLSs for TG were 1.4, 2.0, and 1.9 (70.0, 83.5, 82.5 cM) in F1, F2, and F1+F2, respectively. This TG peak overlaps with an F1 Chr 20 linkage peak (MLS = 2.3, 69.0 cM), although no or minimal linkage peaks (lod <0.5) were found in the QTL regions on Chr 3 and 7.