Evidence of pleiotropic loci for fasting insulin, total fat mass, and abdominal visceral fat in a sedentary population: The HERITAGE Family Study

Objective: To examine whether there is a major gene effect on fasting insul in and pleiotropic loci for fasting insulin, total fat mass (FM), and abdom inal visceral fat (AVF). Research Methods and Procedures: A major gene hypothesis for fasting plasma insulin levels was assessed using segregation analyses of data on 495 memb ers in 98 normolipidemic sedentary families of white descent who participat ed in the HERITAGE Family Study. Results: Segregation analyses were performed on insulin adjusted for age, o n insulin adjusted for age and FM, and on insulin adjusted for age and AVF. Before adjustment for AVF and FM, a major gene effect on fasting insulin l evels was indicated. The putative locus accounted for 54% of the variance u nder a recessive inheritance pattern, affecting 11% of the sample (i.e., al lele frequency = 0.33). However, after adjusting for the effects of AVF or FM, neither a major effect alone nor a multifactorial component alone could be rejected, and support for a major gene was equivocal, i.e., neither the hypothesis of Mendelian tau values or that of the equal tau s were rejecte d and the equal tau model fit the data better than the Mendelian tau model. This pattern (i.e., major gene evidence for insulin before but not after a djustment for AVF or FM) suggests that there is a putative locus with pleio tropic effects on both insulin and FM and another pleiotropic locus for bot h insulin and AVF, Discussion: Although these data do not directly support an additional major gene for insulin independent of AVF and FM, such support cannot be ruled o ut because there is still a significant major effect on FM- or AVF-adjusted insulin (albeit the Mendelian nature of this effect is ambiguous).