Evidence for a Type 2 Diabetes Susceptibility Locus on Chromosome 6 in a Phenotypically Unique Subset of Finnish Subjects.
RICHARD M. WATANABE*, KAREN L. MOHLKE, KAISA SILANDER, HEATHER M. STRINGHAM, TIMO T. VALLE, JAAKKO TUOMILEHTO*, FRANCIS S. COLLINS, RICHARD N. BERGMAN* and MICHAEL BOEHNKE for the FUSION Study. Los Angeles, CA; Ann Arbor, MI; Bethesda, MD; and Helsinki, Finland.
Etiologic heterogeneity may reduce power to detect linkage in type 2 diabetes. Analysis of sub- phenotype data may identify phenotypically more homogeneous subsets, thus improving genetic homogeneity and statistical power. We applied ordered subsets analysis (OSA) to two independent collections of Finnish families (FAM) from the FUSION study. The first collection (F1) consisted of 580 FAM (1240 affecteds (AFF)) and the second collection (F2) had 275 FAM (602 AFF); both genotyped at ~10 cM density. Probable cases of type 1 diabetes were excluded. Linkage analysis using Genehunter-Plus revealed weak linkage to chromosome 6 in F1 (LOD=0.69@99 cM) and stronger evidence in F2 (LOD=1.91@ 101 cM). In F1, OSA revealed two subsets with strong evidence for linkage; 60 FAM with lowest fasting glucose (LOD=4.84@130 cM) and 109 FAM with highest HDL ratio (HDL/total cholesterol; LOD=3.56@86 cM). In F2, OSA revealed two subsets; 88 FAM with lowest fasting insulin (LOD=4.46@101 cM) and 42 FAM with highest HDL ratio (LOD=4.14@99 cM). Sub- phenotypes of AFF within subsets were compared to AFF in the respective complements. AFF in the subsets had lower BMI, WHR, glucose, insulin, and C-peptide (p<0.003 or better). They also had lower cholesterol, LDL, and triglycerides, and higher HDL and HDL ratio (p<0.0001 or better). Age-of-onset (~52 yrs) or duration of diabetes (~12 yrs) were not different. We conclude there exists a unique subset of Finnish subjects that have a type 2 diabetes phenotype consistent with a primary beta-cell defect, have a relatively good lipid profile, and provide evidence for a susceptibility locus on chromosome 6.