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Diabetes Publish Ahead of Print published online ahead of print July 23, 2007
DOI: 10.2337/db06-1023
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Original Research

A Genome-Wide Linkage Scan of Insulin Level Derived Traits: the Amish Family Diabetes Study

Wen-Chi Hsueh1, Kristi D. Silver2, Toni I. Pollin2, Callum J. Bell3, Jeffrey R. O'Connell2, Braxton D. Mitchell2, and Alan R. Shuldiner2,,4

1 Department of Medicine, School of Medicine, University of California, San Francisco, CA
2 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
3 Axys Pharmaceuticals, La Jolla, CA
4 Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center

Correspondence: wen-chi.hsueh{at}ucsf.edu

Objective:Serum insulin levels are altered in insulin resistance and insulin deficiency, states associated with development of type 2 diabetes. The goal of our study was to identify chromosomal regions likely to harbor genetic determinants of these traits.

Research Design and Methods:We conducted a series of genetic analyses, including genome-wide and fine-mapping linkage studies, based on insulin levels measured during an oral glucose tolerance test (OGTT) in 552 non-diabetic participants in the Amish Family Diabetes Study. Indices of insulin secretion included the insulinogenic index and insulin at 30 minutes post-glucose load (insulin 30), while indices of insulin resistance included HOMA-IR and fasting insulin. Insulin area under the curve (AUC), a measure of both insulin secretion and insulin resistance, was also examined.

Results:All traits were modestly heritable, with heritability estimates ranging from 0.1-0.4 (all p < 0.05). There was significant genetic correlation between fasting insulin and HOMA-IR ({rho}G > 0.86, p < 0.05), and insulin 30 and insulinogenic index ({rho}G = 0.81, p < 0.0001), suggesting that common genes influence variation in these pairs of traits. Suggestive linkage signals in the genome scan were to insulin 30 on chromosome 15q23 (LOD = 2.53, p = 0.00032), and to insulinogenic index on chromosome 2p13 (LOD = 2.51, p = 0.00034). Fine-mapping study further refined our signal for insulin 30 on chromosome 15 (LOD = 2.38 at 68 cM).

Conclusions:These results suggest that there may be different genes influencing variation in OGTT measures of insulin secretion and insulin resistance.


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Copyright © 2007 by the American Diabetes Association.