A major gene effect on fasting insulin and insulin sensitivity in familialcombined hyperlipidemia

The most common inherited dyslipidemia, familial combined hyperlipidemia (F CHL), is associated with insulin resistance. Whether insulin sensitivity in these families is inherited is not known. Therefore, we investigated the i nheritance of insulin sensitivity in 352 nondiabetic family members from 37 families with FCHL, 105 of whom had undergone testing using the hyperinsul inemic-euglycemic clamp technique for the measurement of insulin sensitivit y. First, complex segregation analysis of fasting insulin levels (both unad justed and age-, age(2)-, and BMI-adjusted) was used for modeling of the va riance in fasting insulin levels. In these analyses, Mendelian codominant i nheritance (P = 0.320 for unadjusted and P = 0.295 for adjusted insulin val ues) was not rejected over the most general model and fit the data signific antly better than the sporadic model (P < 0.001). Polygenic and environment al models were rejected (P < 0.001). The Mendelian codominant model explain ed 44 and 45% of the variance in unadjusted and adjusted fasting insulin le vels, respectively. The proposed genotypes of this locus, based on segregat ion analysis, were associated with directly measured insulin sensitivity in 105 FCHL family members who underwent the hyperinsulinemic-euglycemic clam p (P < 0.001). These results provide evidence for a major gene regulating i nsulin sensitivity in FCHL families. Possible pleiotropic effects of this i nsulin sensitivity locus on dyslipidemias in FCHL remain to be elucidated.