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Published online February 5, 2008
Diabetes 57:1093-1100, 2008
DOI: 10.2337/db07-1169
© 2008 by the American Diabetes Association
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Quantitative Trait Analysis of Type 2 Diabetes Susceptibility Loci Identified From Whole Genome Association Studies in the Insulin Resistance Atherosclerosis Family Study

Nicholette D. Palmer1,2, Mark O. Goodarzi3, Carl D. Langefeld4, Julie Ziegler4, Jill M. Norris5, Steven M. Haffner6, Michael Bryer-Ash7,8, Richard N. Bergman9, Lynne E. Wagenknecht4, Kent D. Taylor3, Jerome I. Rotter3, and Donald W. Bowden1,2,10

1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
4 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
5 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado
6 Department of Medicine, University of Texas, Health Sciences Center at San Antonio, San Antonio, Texas
7 Gonda (Goldschmied) Diabetes Center, David Geffen School of Medicine at UCLA, Los Angeles, California
8 Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, California
9 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
10 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu

Abbreviations: AIR, acute insulin response; ALX4, aristaless-like 4; CDKAL1, cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1; CDKN2B/CDKN2A, cyclin-dependent kinase inhibitor 2A/B; EXT2, exostosin 2; FSIGT, frequently sampled intravenous glucose tolerance test; FTO, fat mass- and obesity-associated; GWA, genome-wide association; HHEX, hematopoietically expressed homeobox; IDE, insulin-degrading enzyme; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2; IRAS-FS, Insulin Resistance Atherosclerosis Family Study; KIF11, kinesin family member 11; MAF, minor allele frequency; PKN2, protein kinase N2; SI, insulin sensitivity index; SLC30A8, solute carrier family 30, member 8; SNP, single nucleotide polymorphism

OBJECTIVE—Evaluate type 2 diabetes susceptibility variants identified from genome-wide association studies in Hispanic Americans and African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) for association with quantitative measures of glucose homeostasis and determine their biological role in vivo.

RESEARCH DESIGN AND METHODS—Seventeen type 2 diabetes–associated single nucleotide polymorphisms (SNPs) were genotyped in 1,268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis, including insulin sensitivity index (SI), acute insulin response (AIR), and disposition index.

RESULTS—Previously identified risk variants in cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) were associated with reduced AIR (P < 0.0046) in Hispanic Americans. Additionally in Hispanic Americans, the variant in a hypothetical gene (chromosome 11; LOC387761) was significantly associated with AIR (P = 0.0046) with the risk allele showing protective effects, i.e., increased AIR. In both Hispanic- and African-American populations, risk variants at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased disposition index (P < 0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased disposition index (P = 0.011) exclusively in Hispanic Americans.

CONCLUSIONS—These data indicate a distinct, limited number of diabetes-related genes, more specifically the SNPs in the genes identified in European-derived populations, with modest evidence for association with glucose homeostasis traits in Hispanic Americans and African Americans. We observe evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated through defects in insulin secretion. The mechanisms of other predisposing genes remain to be elucidated.


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