Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans

Aims/hypothesisResistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations.MethodsWe examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotype-based promoter activity assays and the gel electrophoretic mobility shift assay.ResultsThe −420G and the −537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (−537A and −420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the −420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects.Conclusions/interpretationPolymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans.

[1]  T. Willson,et al.  Adipose Tissue Resistin Expression Is Severely Suppressed in Obesity and Stimulated by Peroxisome Proliferator-activated Receptor γ Agonists* , 2001, The Journal of Biological Chemistry.

[2]  S. O’Rahilly,et al.  Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. , 2001, Diabetes.

[3]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[4]  A. Doria,et al.  Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians. , 2002, The Journal of clinical endocrinology and metabolism.

[5]  L. Rossetti,et al.  Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. , 2003, The Journal of clinical investigation.

[6]  B. Dallapiccola,et al.  An ATG repeat in the 3'-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance. , 2002, The Journal of clinical endocrinology and metabolism.

[7]  M. Lazar,et al.  A family of tissue-specific resistin-like molecules. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  B. Popkin,et al.  The nutrition transition in South Korea. , 2000, The American journal of clinical nutrition.

[9]  F. Peale,et al.  FIZZ1, a novel cysteine‐rich secreted protein associated with pulmonary inflammation, defines a new gene family , 2000, The EMBO journal.

[10]  U. Smith,et al.  Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. , 2001, Biochemical and biophysical research communications.

[11]  H. Onuma,et al.  Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes. , 2002, Diabetes.

[12]  A. Goodridge,et al.  Effect of the CCAAT/enhancer binding protein on expression of the gene for chicken malic enzyme. , 1999, Archives of biochemistry and biophysics.

[13]  K. Park,et al.  Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. , 2004, The Journal of clinical endocrinology and metabolism.

[14]  Steven R Smith,et al.  A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. , 2003, Diabetes.

[15]  Scott M. Williams,et al.  5' flanking variants of resistin are associated with obesity. , 2002, Diabetes.

[16]  C. Juan,et al.  Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. , 2001, Biochemical and biophysical research communications.

[17]  H. Sul,et al.  A Cysteine-rich Adipose Tissue-specific Secretory Factor Inhibits Adipocyte Differentiation* , 2001, The Journal of Biological Chemistry.

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

[19]  M. Arca,et al.  Human resistin gene, obesity, and type 2 diabetes: mutation analysis and population study. , 2002, Diabetes.

[20]  M. Lazar,et al.  The hormone resistin links obesity to diabetes , 2001, Nature.

[21]  Jong Bae Seo,et al.  Functional characterization of the human resistin promoter with adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element binding protein 1c and CCAAT enhancer binding protein-alpha. , 2003, Molecular endocrinology.

[22]  Arya M. Sharma,et al.  Resistin gene expression in human adipocytes is not related to insulin resistance. , 2002, Obesity research.

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

[24]  R. Hegele,et al.  Single nucleotide polymorphisms of the resistin (RSTN) gene , 2001, Journal of Human Genetics.

[25]  W. Chu,et al.  Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. , 2002, The Journal of clinical endocrinology and metabolism.

[26]  Jong Bae Seo,et al.  Functional characterization of the human resistin promoter with adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element binding protein 1c and CCAAT enhancer binding protein-alpha. , 2003, Molecular endocrinology.

[27]  I. Castan-Laurell,et al.  Decreased resistin expression in mice with different sensitivities to a high-fat diet. , 2001, Biochemical and biophysical research communications.

[28]  S. Antonarakis,et al.  Nomenclature for the description of human sequence variations , 2001, Human Genetics.

[29]  E. Boerwinkle,et al.  Bias of the contribution of single-locus effects to the variance of a quantitative trait. , 1986, American journal of human genetics.