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Quantitative Trait Analysis of T2D Susceptibility Loci Identified from Whole Genome Association Studies in the IRAS Family Study

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

Objective: Evaluate type 2 diabetes (T2D) susceptibility variants identified from genome-wide association (GWA) 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 T2D-associated SNPs were genotyped in 1268 Hispanic- and 581 African-American participants from the IRAS-FS. SNPs were tested for association with quantitative measures of glucose homeostasis including: insulin sensitivity (S_I), acute insulin response (AIR) and disposition index (DI).

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 SLC30A8 locus were nominally associated with decreased DI (P<0.078). Risk variants in the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) locus were associated with a decreased DI (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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