Genomic scan of glucose and insulin metabolism phenotypes: The HERITAGE Family Study

Genetic factors play a role in the regulation of glucose metabolism-related traits such as insulin sensitivity (S_I), insulin secretion, and glucose effectiveness (S_G). Several genomic scans have been performed to localize genes involved in glucose metabolism-related traits. However, few of these studies have been performed with phenotypes derived from the frequently sampled intravenous glucose tolerance test (IVGTT) using the minimal modeling (MINMOD) approach. Here, we report on such a scan for glucose metabolism-related traits derived from MINMOD analysis of IVGTT data in 322 sibling pairs from 95 sedentary white families and 75 sibling pairs from 49 sedentary black families from the HERITAGE Family Study. In addition to S_I and S_G, we also considered acute insulin response to a glucose challenge (AIR_Glucose), which is an index for insulin secretion, and disposition index (DI, product of S_I and AIR_Glucose), which is a measure of the activity of pancreatic β cells corrected for insulin resistance. These traits were adjusted for age, sex, and body mass index (BMI) in each of 8 sex-by-generation-by-race groups, and then standardized residuals were used as the phenotypes in the linkage analyses. Analyses were with the multipoint variance components linkage method, as implemented in the computer program SEGPATH, using 509 markers. Several regions with promising linkages (LOD score ≥ 1.75, P ≤ .0023) were detected. They include five regions (1q41 and 8p23.2 for S_I, 4q32.1 and 10p15.3 for AIR_Glucose, and 13q32.1 for DI) in whites and 2 regions (9p11.2 for S_G and 10q26.11 for S_I) in blacks. Three of these regions (4q32.1, 9p11.2, 10p15.3) are likely to harbor genes that influence interindividual variation in glucose metabolism-related traits as they replicate findings from other studies. Fine mapping and association studies of candidate genes within these genomic regions are warranted.