Quantitative trait loci on chromosome 8q24 for pancreatic beta-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.

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 beta-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 beta-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 beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-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.

[1]  R. Bergman,et al.  Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study , 2005, Diabetologia.

[2]  J. Pankow,et al.  Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families , 2005, Diabetologia.

[3]  E. Boerwinkle,et al.  Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. , 2005, Diabetes.

[4]  N. Risch,et al.  Admixture mapping for hypertension loci with genome-scan markers , 2005, Nature Genetics.

[5]  G. Chase,et al.  Genome scan meta-analysis for hypertension. , 2004, American journal of hypertension.

[6]  M. Ng,et al.  Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. , 2004, Diabetes.

[7]  R. Bergman,et al.  Identification of Quantitative Trait Loci for Glucose Homeostasis The Insulin Resistance Atherosclerosis Study (IRAS) Family Study , 2022 .

[8]  J. Levy,et al.  Use and abuse of HOMA modeling. , 2004, Diabetes care.

[9]  Carl D Langefeld,et al.  A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q. , 2004, Diabetes.

[10]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[11]  Donald W. Bowden,et al.  A Genome-Wide Scan for Type 2 Diabetes in African-American Families Reveals Evidence for a Locus on Chromosome 6 q , 2004 .

[12]  Daniel J Zaccaro,et al.  Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. , 2003, Diabetes.

[13]  C. Bouchard,et al.  Genomic scan of glucose and insulin metabolism phenotypes: the HERITAGE Family Study. , 2003, Metabolism: clinical and experimental.

[14]  M A Province,et al.  Multivariate and multilocus variance components method, based on structural relationships to assess quantitative trait linkage via SEGPATH , 2003, Genetic epidemiology.

[15]  M. Ellenberg,et al.  Ellenberg and Rifkin's Diabetes Mellitus , 2002 .

[16]  D. Matthews,et al.  The assessment of insulin resistance in man , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[17]  C. Bouchard,et al.  Genomewide Linkage Scan of Resting Blood Pressure: HERITAGE Family Study , 2002, Hypertension.

[18]  D. Richman,et al.  Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections , 2002, Nature Medicine.

[19]  M. Cooper,et al.  Hypertension and diabetes , 2002, Current opinion in nephrology and hypertension.

[20]  J. Houwing-Duistermaat,et al.  A genome-wide search for linkage-disequilibrium with type 1 diabetes in a recent genetically isolated population from the Netherlands. , 2002, Diabetes.

[21]  R. Bergman,et al.  Accurate Assessment of β-Cell Function: The Hyperbolic Correction , 2002 .

[22]  S. O’Rahilly,et al.  Digenic inheritance of severe insulin resistance in a human pedigree , 2002, Nature Genetics.

[23]  T. Buchanan,et al.  Coincident Linkage of Fasting Plasma Insulin and Blood Pressure to Chromosome 7q in Hypertensive Hispanic Families , 2001, Circulation.

[24]  R Foxon,et al.  A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. , 2001, American journal of human genetics.

[25]  D. Matthews.  Insulin resistance and β‐cell function – a clinical perspective , 2001 .

[26]  M A Province,et al.  Tree‐based recursive partitioning methods for subdividing sibpairs into relatively more homogeneous subgroups , 2001, Genetic epidemiology.

[27]  M. Province,et al.  19 Classification methods for confronting heterogeneity , 2001 .

[28]  M. Province,et al.  Classification methods for confronting heterogeneity. , 2001, Advances in genetics.

[29]  H M Stringham,et al.  The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci. , 2000, American journal of human genetics.

[30]  M A Province,et al.  NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. , 2000, Annals of epidemiology.

[31]  R C Elston,et al.  Haseman and Elston revisited , 2000, Genetic epidemiology.

[32]  T. Hansen,et al.  Polymorphism in the glycogen-associated regulatory subunit of type 1 protein phosphatase (PPP1R3) gene and insulin sensitivity. , 2000, Diabetes.

[33]  M A Province,et al.  The Future of Path Analysis, Segregation Analysis, and Combined Models for Genetic Dissection of Complex Traits , 1999, Human Heredity.

[34]  L. Almasy,et al.  Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. , 1999, American journal of human genetics.

[35]  J. Levy,et al.  Correct Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program , 1998, Diabetes Care.

[36]  S. Scherer,et al.  Variation in the AU(AT)-rich element within the 3'-untranslated region of PPP1R3 is associated with variation in plasma glucose in aboriginal Canadians. , 1998, The Journal of clinical endocrinology and metabolism.

[37]  M. Ehm,et al.  An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. , 1998, American journal of human genetics.

[38]  E. Lander,et al.  Complete multipoint sib-pair analysis of qualitative and quantitative traits. , 1995, American journal of human genetics.

[39]  T. Hansen,et al.  A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. , 1995, Human molecular genetics.

[40]  C. Granier,et al.  Epitope mapping and binding analysis of insulin-specific monoclonal antibodies using a biosensor approach. , 1995, Journal of immunological methods.

[41]  M A Province,et al.  General purpose model and a computer program for combined segregation and path analysis (SEGPATH): Automatically creating computer programs from symbolic language model specifications , 1995, Genetic epidemiology.

[42]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[43]  M. Zemel,et al.  Hypertension and diabetes. , 1988, The Medical clinics of North America.

[44]  K. Liang,et al.  Asymptotic Properties of Maximum Likelihood Estimators and Likelihood Ratio Tests under Nonstandard Conditions , 1987 .

[45]  R. Elston,et al.  The investigation of linkage between a quantitative trait and a marker locus , 1972, Behavior genetics.