Identification of Quantitative Trait Loci for Glucose Homeostasis

Abstract

Genetic and environmental determinants play critical roles in insulin resistance and ␤-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity (S I ), glucose disposition (S G ), acute insulin response to glucose (AIR G ), and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. A genome scan for glucose homeostasis phenotypes in nondiabetic subjects has been carried out in African-American (n ‫؍‬ 21) and Hispanic (n ‫؍‬ 45) extended families as part of the IRAS Family Study. In African-American families, there was significant evidence for linkage of DI between D11S2371 and D11S2002 (logarithm of odds [LOD] ‫؍‬ 3.21) at 81 cM, and in the combined sample of African-American and Hispanic families, there was evidence at GATA117D01 (140 cM) on chromosome 11 (LOD ‫؍‬ 2.21). Evidence of linkage was also observed for S I in Hispanic (LOD ‫؍‬ 2.28, between D15S822 and GTTTT001) and AIR G in African-American families (LOD ‫؍‬ 2.73, between D4S1625 and D4S1629; and LOD ‫؍‬ 2.56 at PAH (phenylalanine hydroxylase) on chromosome 12). These results provide impetus for future positional cloning of quantitative trait loci (QTLs). Identifying genes in these regions should provide insight into the nature of the metabolic syndrome and diabetes, and facilitate the development of more effective therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.

Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS family study

“…Each pedigree was examined for consistency of stated family structure and is described in detail elsewhere. 23 Maximum likelihood estimates of allele frequencies were computed using the largest set of unrelated individuals and tested for departures from Hardy-Weinberg equilibrium proportions. Each of the SNPs evaluated in this work were examined for Mendelian inconsistencies in their genotypes using PEDCHECK.…”

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

“…The clustering of these metabolic traits along with their heritable features suggests that defects in one or more genes may contribute to metabolic syndrome. Linkage analysis has been widely adopted to narrow down the broad chromosomal regions harbouring susceptibility loci and to elucidate genetic features of various metabolic phenotypes, as well as to categorically define metabolic syndrome [7][8][9]. The results, however, are mostly limited to identifying: (1) regions with logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait that are of merely marginal significance; or (2) regions with modest contributions to overall trait variation [10].…”

Orchestration of Glucose Homeostasis

“…Insulin resistance is an important risk factor, necessary but not sufficient to cause the disease. There may be a genetic component to resistance (36), but many nongenetic factors can contribute, including obesity (particularly truncal obesity), lack of exercise, onset of puberty, pregnancy, and a group of conditions and therapies such as polycystic ovarian syndrome, infection, and treatment for HIV. We are now aware that a reduced compensatory response of insulin secretion in the face of insulin resistance is necessary for the development of frank type 2 diabetes.…”