Bivariate Linkage Analysis of the Insulin Resistance Syndrome Phenotypes on Chromosome 7q

Metabolic abnormalities of the insulin resistance syndrome (IRS) have been shown to aggregate in families and to exhibit trait-pair correlations, suggesting a common genetic component. A broad region on chromosome 7q has been implicated in several studies to contain loci that cosegregate with IRS-related traits. However, it is not clear whether such loci have any common genetic (pleiotropic) influences on the correlated traits. Also, it is not clear whether the chromosomal regions contain more than one locus influencing the IRS-related phenotypes. In this study we present evidence for linkage of five IRS-related traits [body mass index (BMI), waist circumference (WC), ln split proinsulin (LSPI), ln triglycerides (LTG), and high-density lipoprotein cholesterol (HDLC)] to a region at 7q11.23. Subsequently, to gain further insight into the genetic component(s) mapping to this region, we explored whether linkage of these traits is due to pleiotropic effects using a bivariate linkage analytical technique, which has been shown to localize susceptibility regions with precision. Four hundred forty individuals from 27 Mexican American families living in Texas were genotyped for 19 highly polymorphic markers on chromosome 7. Multipoint variance component linkage analysis was used to identify genetic location(s) influencing IRS-related traits of obesity (BMI and WC), dyslipidemia (LTG and HDLC), and insulin levels (LSPI); the analysis identified a broad chromosomal region spanning approximately 24 cM. To gain more precision in localization, we used a bivariate linkage approach for each trait pair. These analyses suggest localization of most of these bivariate traits to an approximately 6-cM region near marker D7S653 [7q11.23, 103–109 cM; a maximum bivariate LOD of 4.51 was found for the trait pair HDLC and LSPI (the LODeq score is 3.94)]. We observed evidence of pleiotropic effects in this region on obesity and insulin-related trait pairs.

[1]  E. Pugh,et al.  A study of linkage and association of body mass index in the old order Amish , 2003, American journal of medical genetics. Part C, Seminars in medical genetics.

[2]  Hongyu Zhao,et al.  Linkage and linkage disequilibrium mapping of genes influencing human obesity in chromosome region 7q22.1-7q35. , 2003, Diabetes.

[3]  Robert L Hanson,et al.  Components of the "metabolic syndrome" and incidence of type 2 diabetes. , 2002, Diabetes.

[4]  David M. Evans,et al.  The power of multivariate quantitative-trait loci linkage analysis is influenced by the correlation between variables. , 2002, American journal of human genetics.

[5]  I. Borecki,et al.  A combined analysis of genomewide linkage scans for body mass index from the National Heart, Lung, and Blood Institute Family Blood Pressure Program. , 2002, American journal of human genetics.

[6]  P. O'Connell,et al.  Factors of insulin resistance syndrome--related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic mexican-americans. , 2002, Diabetes.

[7]  A. Glazier,et al.  Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism , 2002, Mammalian Genome.

[8]  Kyosuke Yamamoto,et al.  Association of the Pro90Ser CD36 mutation with elevated free fatty acid concentrations but not with insulin resistance syndrome in Japanese. , 2001, Clinica chimica acta; international journal of clinical chemistry.

[9]  R. Silverstein,et al.  CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. , 2001, The Journal of clinical investigation.

[10]  M. Tuck,et al.  Selective aspects of the insulin resistance syndrome , 2001, Current opinion in nephrology and hypertension.

[11]  P. O'Connell,et al.  A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. , 2001, American journal of human genetics.

[12]  Mariza de Andrade,et al.  Comparison of Multivariate Tests for Genetic Linkage , 2001, Human Heredity.

[13]  J. Weber,et al.  Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. O'Connell,et al.  A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. , 2000, American journal of human genetics.

[15]  P. van Eerdewegh,et al.  Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results. , 1999, American journal of human genetics.

[16]  K. Kendler,et al.  Replication of linkage studies of complex traits: an examination of variation in location estimates. , 1999, American journal of human genetics.

[17]  PäiviLempiäinen,et al.  Insulin Resistance Syndrome Predicts Coronary Heart Disease Events in Elderly Nondiabetic Men , 1999 .

[18]  P. Savage,et al.  Risk factor clustering in the insulin resistance syndrome. The Strong Heart Study. , 1998, American journal of epidemiology.

[19]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[20]  Ralph B D'Agostino,et al.  Risk Variable Clustering in the Insulin Resistance Syndrome: The Framingham Offspring Study , 1997, Diabetes.

[21]  W. Chung,et al.  Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7. , 1996, American journal of human genetics.

[22]  J. Blangero,et al.  Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[23]  S. Haffner,et al.  Predicting Diabetes: Moving Beyond Impaired Glucose Tolerance , 1993, Diabetes.

[24]  S. Haffner,et al.  Incidence of NIDDM and Impaired Glucose Tolerance in Hypertensive Subjects: The San Antonio Heart Study , 1993, Diabetes.

[25]  R. DeFronzo,et al.  Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease , 1991, Diabetes Care.

[26]  G. Reaven.  Banting lecture 1988. Role of insulin resistance in human disease. , 1988, Diabetes.

[27]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

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

[29]  S. Haffner,et al.  Do Upper-Body and Centralized Adiposity Measure Different Aspects of Regional Body-Fat Distribution? Relationship to Non-Insulin-Dependent Diabetes Mellitus, Lipids, and Lipoproteins , 1987, Diabetes.

[30]  Donna K Arnett,et al.  Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. , 2002, American journal of human genetics.

[31]  R. Silverstein,et al.  CD 36 : a class B scavenger receptor involved in angiogenesis , atherosclerosis , inflammation , and lipid metabolism , 2001 .

[32]  J. Blangero,et al.  Replication of Linkage to Quantitative Trait Loci: Variation in Location and Magnitude of the Lod Score , 2001, Genetic epidemiology.

[33]  James Scott,et al.  Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats , 1999, Nature Genetics.

[34]  L. Almasy,et al.  Bivariate quantitative trait linkage analysis: Pleiotropy versus co‐incident linkages , 1997, Genetic epidemiology.

[35]  J. Blangero,et al.  Major gene with sex‐specific effects influences fat mass in Mexican Americans , 1995, Genetic epidemiology.

[36]  K. Lange,et al.  Ascertainment and goodness of fit of variance component models for pedigree data. , 1984, Progress in clinical and biological research.