Genetic variation in the visfatin gene (PBEF1) and its relation to glucose metabolism and fat-depot-specific messenger ribonucleic acid expression in humans.

CONTEXT AND OBJECTIVE Visfatin is a peptide suggested to play a role in glucose homeostasis. In the present study, we investigated the role of genetic variation in the visfatin gene in the pathophysiology of obesity/type 2 diabetes mellitus (T2DM). DESIGN The visfatin gene (PBEF1) was sequenced in DNA samples from 24 nonrelated Caucasian subjects. Identified genetic variants were used for association analyses of T2DM in a case-control study (503 diabetic subjects and 476 healthy controls) and T2DM-related traits in 626 nondiabetic subjects. The effect of genetic variation in the visfatin gene on its mRNA expression in a subgroup of 157 nondiabetic subjects with measurements of visfatin mRNA expression in visceral and sc fat depots was also analyzed. RESULTS Seven single-nucleotide polymorphisms (SNPs) and one insertion/deletion were identified. Three SNPs (rs9770242, -948G-->T, rs4730153) that were representatives of their linkage disequilibrium groups were genotyped in Caucasians from Germany with a wide range of body fat distribution and insulin sensitivity for association analyses. No association of T2DM with any of the genotyped SNPs or their haplotypes was found. However, the ratio of visceral/sc visfatin mRNA expression was associated with all three genetic polymorphisms (P < 0.05). Moreover, the -948G-->T variant was associated with 2-h plasma glucose and fasting insulin concentrations (P < 0.05) in nondiabetic subjects. CONCLUSIONS In conclusion, our data suggest that genetic variation in the visfatin gene may have a minor effect on visceral and sc visfatin mRNA expression profiles but does not play a major role in the development of obesity or T2DM.

[1]  M. Fasshauer,et al.  Plasma visfatin concentrations and fat depot-specific mRNA expression in humans. , 2005, Diabetes.

[2]  H. Lodish,et al.  Visfatin: A New Adipokine , 2005, Science.

[3]  M. Matsuda,et al.  Visfatin: A Protein Secreted by Visceral Fat That Mimics the Effects of Insulin , 2005, Science.

[4]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, 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]  R. Paschke,et al.  Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes , 2002, Diabetologia.

[8]  Jiandie D. Lin,et al.  Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β), A Novel PGC-1-related Transcription Coactivator Associated with Host Cell Factor* , 2002, The Journal of Biological Chemistry.

[9]  S. Ognjanovic,et al.  Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes. , 2001, Journal of molecular endocrinology.

[10]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[11]  B. Wajchenberg.  Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. , 2000, Endocrine reviews.

[12]  K. Frayn.  Visceral fat and insulin resistance — causative or correlative? , 2000, British Journal of Nutrition.

[13]  Gonçalo R. Abecasis,et al.  GOLD-Graphical Overview of Linkage Disequilibrium , 2000, Bioinform..

[14]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[15]  S. O’Rahilly,et al.  Depot-related gene expression in human subcutaneous and omental adipocytes. , 1998, Diabetes.

[16]  P. Eriksson,et al.  Leptin secretion from subcutaneous and visceral adipose tissue in women. , 1998, Diabetes.

[17]  A. Greenberg,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Omental and Subcutaneous Adipose Tissues of Obese Subjects Release Interleukin-6: Depot Difference and Regulation by Glucocorticoid* , 1997 .

[18]  P. Morange,et al.  Production of Plasminogen Activator Inhibitor 1 by Human Adipose Tissue: Possible Link Between Visceral Fat Accumulation and Vascular Disease , 1997, Diabetes.

[19]  I McNiece,et al.  Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor , 1994, Molecular and cellular biology.

[20]  P. Björntorp.  Metabolic Implications of Body Fat Distribution , 1991, Diabetes Care.

[21]  S. Kliewer,et al.  Retinoic acid is a negative regulator of AP-1-responsive genes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Peter Angel,et al.  The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1 , 1988, Cell.

[23]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[24]  K. Calame,et al.  An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. , 1994, Nucleic acids research.