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Quantitative Trait Loci on Chromosome 8q24 for Pancreatic ß-Cell Function and 7q11 for Insulin Sensitivity in Obese Nondiabetic White and Black Families

Evidence From Genome-Wide Linkage Scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) Study

¹ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
² Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri
³ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁴ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁵ Division of Epidemiology, University of Minnesota, Minneapolis, Minnesota
⁶ Department of Neurology, Boston Medical Center, Boston, Massachusetts
⁷ Departments of Medicine and Obstetrics/Gynecology, Cedars-Sinai Medical Center and UCLA, Los Angeles, California
⁸ Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah

Address correspondence and reprint requests to Ping An, MD, Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine (Campus Box 8067), 660 South Euclid Ave., St. Louis, MO 63110. E-mail: anping{at}wustl.edu

Key Words: BCF, ß-cell function • FBPP, Family Blood Pressure Program • HOMA, homeostasis model assessment • HyperGEN, Hypertension Genetic Epidemiology Network • LOD, logarithm of odds • QTL, quantitative trait locus

Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic ß-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid–lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For ß-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of ß-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for ß-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes–associated traits.

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