A Major Gene Effect on Fasting Insulin and Insulin Sensitivity in Familial Combined Hyperlipidemia

Abstract

The most common inherited dyslipidemia, familial combined hyperlipidemia (FCHL), is associated with insulin resistance. Whether insulin sensitivity in these families is inherited is not known. Therefore, we investigated the inheritance of insulin sensitivity in 352 nondiabetic family members from 37 families with FCHL, 105 of whom had undergone testing using the hyperinsulinemiceuglycemic clamp technique for the measurement of insulin sensitivity. First, complex segregation analysis of fasting insulin levels (both unadjusted and age-, age 2 -, and BMI-adjusted) was used for modeling of the variance in fasting insulin levels. In these analyses, Mendelian codominant inheritance (P ‫؍‬ 0.320 for unadjusted and P ‫؍‬ 0.295 for adjusted insulin values) was not rejected over the most general model and fit the data significantly better than the sporadic model (P < 0.001). Polygenic and environmental models were rejected (P < 0.001). The Mendelian codominant model explained 44 and 45% of the variance in unadjusted and adjusted fasting insulin levels, respectively. The proposed genotypes of this locus, based on segregation analysis, were associated with directly measured insulin sensitivity in 105 FCHL family members who underwent the hyperinsulinemic-euglycemic clamp (P < 0.001). These results provide evidence for a major gene regulating insulin sensitivity in FCHL families. Possible pleiotropic effects of this insulin sensitivity locus on dyslipidemias in FCHL remain to be elucidated. Diabetes 50:2396 -2401, 2001 F amilial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia and is associated with increased risk of cardiovascular diseases (1). The prevalence in Western populations is reported to be ϳ1%, but in patients who have coronary heart disease at young age, the prevalence may be as high as 20% (2,3). FCHL is characterized by different types of dyslipidemias (2,3) and insulin resistance (4 -8). Most likely, FCHL is an oligogenic disorder (8,9). Major genes for triglycerides (2,10), apolipoprotein B (apoB) (11-13), and small, dense LDL (14,15) have been proposed, but so far no major genes for these traits have been mapped. However, several loci identified in genome-wide random searches have been proposed to modify lipid levels (16 -18).Insulin resistance, defined as insulin's impaired ability to exert its normal function (19), can be quantified directly with the hyperinsulinemic-euglycemic clamp (20). In Pima Indians, insulin sensitivity measured by this technique has been reported to be distributed as a mixture of three normal distributions. This suggests that a major codominant gene may determine insulin sensitivity (21). Because the clamp study is difficult to perform in large families with several generations, fasting insulin level has been used as a surrogate of insulin action (22). Using segregation analysis in families randomly ascertained (23) or through siblings with type 2 diabetes (24), major genes have been proposed to determine fasting and postglucose insulin levels. These segregati...

Confirmed Locus on Chromosome 11p and Candidate Loci on 6q and 8p for the Triglyceride and Cholesterol Traits of Combined Hyperlipidemia

“…Type 2 diabetes was a specific exclusion criterion in the present study. However, because previous studies have indicated that patients with FCHL may have impaired glucose tolerance and insulin resistance, 8,19,21,24,40,41 some of the linkage signals we obtained close to this marker in our analyses might relate to a common metabolic abnormality in FCHL and type 2 diabetes.…”

Role of Insulin Resistance in Familial Combined Hyperlipidemia

“…Indeed, recently, a major gene effect on insulin resistance in FCH has been suggested. 16 FCH is characterized by multiple lipoprotein phenotype expression; in 1 affected family, subjects may present with hyperTC, hyperTG or combined HLP. We demonstrate that insulin resistance is associated with lipid phenotype expression because FCH subjects based on hyperTG or combined HLP, were more insulin resistant compared with FCH subjects based on hyperTC.…”

“…Previous studies have shown that FCH subjects are insulin resistant. [12][13][14][15][16][17][18] The aim of this study was to explore the role of insulin resistance in FCH lipid phenotype expression. Therefore, we studied in our large FCH cohort FCH subjects with different lipid phenotypes and the effect of changes in insulin resistance on intraindividual changes in lipid phenotype over a 5-year period.…”

Diagnostic Criteria in Relation to the Pathogenesis of Familial Combined Hyperlipidemia

“…Segregation analyses have provided evidence for a major gene effect on apoB levels, 10-12 TG levels, 79 and the presence of sdLDL 7,11,15 and insulin resistance. 80 Genome-wide linkage studies have indicated that several chromosomal regions harbor genes that contribute to the lipid profile of FCH. In Finnish families with FCH, five loci on chromosomes 1q21, 2q31, 10p11.2, 10q11.2-10qter, and 21q21 were identified, whereas in Dutch families with FCH four loci on chromosomes 2p, 11p, 16q, and 19q were found.…”