Subsets of Finns with high HDL to total cholesterol ratio show evidence for linkage to type 2 diabetes on chromosome 6q.

Objectives: The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families.

Methods: Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement.

Results: OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM.

Conclusions: These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM.