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Identification of Quantitative Trait Loci for Glucose Homeostasis

The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

¹ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
² Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
⁴ Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado
⁵ Division of Clinical Epidemiology, University of California at Los Angeles, Los Angeles, California
⁶ Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
⁷ Division of Medical Genetics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Burns and Allen Research Institute, Los Angeles, California
⁸ Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California

Genetic and environmental determinants play critical roles in insulin resistance and ß-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.

Abbreviations: AIR_G, acute insulin response to glucose; DI, disposition index; IBD, identity by descent; IRAS, Insulin Resistance Atherosclerosis Study; IVGTT, intravenous glucose tolerance test; LOD, logarithm of odds; MINMOD, minimal model; QTL, quantitative trait locus

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