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Genetic Mapping of Disposition Index and Acute Insulin Response Loci on Chromosome 11q

The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

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 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁴ Department of Medicine, University of California at Los Angeles, Los Angeles, California
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 Medical Genetics Institute, Burns and Allen Cedars-Sinai Research Institute, Los Angeles, California
⁸ Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
⁹ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and 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; DI, disposition index; GEE, generalized estimating equation; IBD, identity-by-descent; IRASFS, Insulin Resistance Atherosclerosis Study Family Study; LOD, logarithm of odds; MAF, minor allele frequency; MLS, maximum LOD score; PC, pyruvate carboxylase; PYGM, muscle glycogen phophorylase; QTL, quantitative trait locus; SNP, single nucleotide polymorphism

Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and ß-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (S_i) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P < 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P < 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region.

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