A major locus for fasting insulin concentrations and insulin resistance onchromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans

Insulin resistance and hyperinsulinemia are strong correlates of obesity an d type 2 diabetes, but little is known about their genetic determinants. Us ing data on nondiabetics from Mexican American families and a multipoint li nkage approach, we scanned the genome and identified a major locus near mar ker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P < .0001), which do not crossreact with insulin precursors. Insulin resis tanc e, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical (P < .0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since se veral insulin-resistance syndrome (IRS)-related phenotypes were mapped inde pendently to the regions on chromosome 6q, we conducted bivariate multipoin t linkage analyses to map the correlated IRS phenotypes. These analyses imp licated the same chromosomal region near marker D6S403 (6q22-q23) as harbor ing a major gene with strong pleiotropic effects on obesity and on lipid me asures, including leptin concentrations (e.g., LODeq for traits-specific in sulin and leptin was 4.7). A positional candidate gene for insulin resistan ce in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q2 5.2-q26), was also identified by the bivariate analysis as exerting signifi cant pleiotropic influences on IRS-related phenotypes (e.g., LODeq for trai ts-specific insulin and leptin was 4.1). This chromosomal region harbors po sitional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In s um, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in M exican Americans.