A Genome-Wide Linkage Scan of Insulin Level–Derived Traits

A Genome-Wide Linkage Scan of Insulin Level–Derived Traits The Amish Family Diabetes Study Wen-Chi Hsueh 1 , Kristi D. Silver 2 , Toni I. Pollin 2 , Callum J. Bell 3 , Jeffrey R. O’Connell 2 , Braxton D. Mitchell 2 and Alan R. Shuldiner 2 4 1 Department of Medicine, School of Medicine, University of California, San Francisco, California 2 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 3 Axys Pharmaceuticals, La Jolla, California 4 Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland Address correspondence and reprint requests to Wen-Chi Hsueh, MPH, PhD, 2200 Post St., C433, San Francisco, CA 94143-1640. E-mail: wen-chi.hsueh{at}ucsf.edu Abstract OBJECTIVE— Serum insulin levels are altered in insulin resistance and insulin deficiency, states that are associated with the development of type 2 diabetes. The goal of our study was to identify chromosomal regions that are 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 nondiabetic participants in the Amish Family Diabetes Study. Indices of insulin secretion included the insulinogenic index and insulin at 30 min postglucose load (insulin 30), while indices of insulin resistance included homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin. Insulin area under the curve, 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 to 0.4 (all P < 0.05). There was significant genetic correlation between fasting insulin and HOMA-IR (ρ G > 0.86, P < 0.05), as well as insulin 30 and insulinogenic index (ρ 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 (logarithm of odds [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. AUC, area under the