Association Study and Mutation Analysis of Adiponectin Shows Association of Variants in APM1 with Complex Obesity in Women

We performed an association study and mutation analysis of the adiponectin (APM1) gene to study its involvement in the development of obesity. We also studied the interaction with peroxisome proliferator‐activated receptor γ (PPARγ). 223 obese women and 87 healthy female control subjects were used for association analysis. Mutation analysis was done on 95 morbidly obese adults and 123 overweight and obese children and adolescents. We selected 6 haplotype tagging SNPs in APM1 and the Pro12Ala variant (rs1805192) in PPARγ to study the interaction. The G allele of rs2241766 was more common in controls (cases 10.8% vs. controls 18.4%, nominal p = 0.011; OR = 0.57, nominal p = 0.018). The rs2241766/rs3774261 haplotype was also associated with obesity (nominal p = 0.004). Only the latter association remained significant after controlling for the False Discovery Rate. Resequencing of exon 2, exon 3 and intron 2 in 95 individuals did not reveal any SNPs in high linkage disequilibrium with rs2241766. No interaction with the Pro12Ala variant in PPARγ was detected. Mutation analysis of APM1 did not identify mutations. In conclusion, we found an association of an APM1 haplotype with obesity and found that APM1 mutations are not a common cause of monogenic obesity in our cohort.

[1]  Lee-Ming Chuang,et al.  Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity , 2003, Journal of Molecular Medicine.

[2]  M. Arca,et al.  Association of the human adiponectin gene and insulin resistance , 2004, European Journal of Human Genetics.

[3]  K. Clément,et al.  Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. , 2002, Human molecular genetics.

[4]  J. H. Lee,et al.  The SNP276G>T polymorphism in the adiponectin (ACDC) gene is more strongly associated with insulin resistance and cardiovascular disease risk than SNP45T>G in nonobese/nondiabetic Korean men independent of abdominal adiposity and circulating plasma adiponectin. , 2006, Metabolism: clinical and experimental.

[5]  T Nakamura,et al.  Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. , 1999, Circulation.

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

[7]  C. Dina,et al.  Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. , 2002, Diabetes.

[8]  Philippe Froguel,et al.  Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation* , 2002, The Journal of Biological Chemistry.

[9]  Y. Nakano,et al.  Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. , 1996, Journal of biochemistry.

[10]  S. Kihara,et al.  Genomic structure and mutations in adipose-specific gene, adiponectin , 2000, International Journal of Obesity.

[11]  A. Tsatsoulis,et al.  Association of the T45G polymorphism in exon 2 of the adiponectin gene with polycystic ovary syndrome: role of Delta4-androstenedione. , 2004, Human reproduction.

[12]  M. Matsuda,et al.  Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 , 2002, Nature Medicine.

[13]  S. Kihara,et al.  Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages , 2001, Circulation.

[14]  S. P. Fodor,et al.  Blocks of Limited Haplotype Diversity Revealed by High-Resolution Scanning of Human Chromosome 21 , 2001, Science.

[15]  M. Stumvoll,et al.  Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. , 2002, Diabetes.

[16]  J. Schölmerich,et al.  Mutation analysis of the human adipocyte‐specific apM‐1 gene , 2000, European journal of clinical investigation.

[17]  Lisa J. Martin,et al.  Interactions between noncontiguous haplotypes in the adiponectin gene ACDC are associated with plasma adiponectin. , 2006, Diabetes.

[18]  C. Block,et al.  Mechanisms linking obesity with cardiovascular disease , 2006, Nature.

[19]  M. Laakso,et al.  An SNP in the adiponectin gene is associated with decreased serum adiponectin levels and risk for impaired glucose tolerance. , 2005, Obesity research.

[20]  M. Laakso,et al.  The common polymorphisms (single nucleotide polymorphism [SNP] +45 and SNP +276) of the adiponectin gene predict the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. , 2005, Diabetes.

[21]  C. Dina,et al.  The adiponectin gene SNP+45 is associated with coronary artery disease in Type 2 (non‐insulin‐dependent) diabetes mellitus , 2004, Diabetic medicine : a journal of the British Diabetic Association.

[22]  T. M. Hsu,et al.  Universal SNP genotyping assay with fluorescence polarization detection. , 2001, BioTechniques.

[23]  P. J. Larsen,et al.  ACDC/Adiponectin and PPAR‐γ Gene Polymorphisms: Implications for Features of Obesity , 2005 .

[24]  U. Müller-Ladner,et al.  Different effects of adiponectin isoforms in human monocytic cells , 2006, Journal of leukocyte biology.

[25]  T. Funahashi,et al.  Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice. , 2003, Diabetes.

[26]  P. J. Larsen,et al.  ACDC/adiponectin and PPAR-gamma gene polymorphisms: implications for features of obesity. , 2005, Obesity research.

[27]  M. Yamagishi,et al.  Association of genetic variation of the adiponectin gene with body fat distribution and carotid atherosclerosis in Japanese obese subjects. , 2007, Journal of atherosclerosis and thrombosis.

[28]  T Nakamura,et al.  Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[29]  S. O’Rahilly,et al.  Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. , 2002, Endocrinology.

[30]  T. Ogihara,et al.  Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. , 2004, Journal of the American College of Cardiology.

[31]  P. Scherer,et al.  A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. , 2002, Diabetes.

[32]  C. Bouchard,et al.  Adiponectin and adiponectin receptor gene variants in relation to resting metabolic rate, respiratory quotient, and adiposity-related phenotypes in the Quebec Family Study. , 2007, The American journal of clinical nutrition.

[33]  M. Matsuda,et al.  Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. , 2002, Diabetes.

[34]  T. Funahashi,et al.  cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). , 1996, Biochemical and biophysical research communications.

[35]  H. Lodish,et al.  Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Hadjadj,et al.  Adiponectin gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3-year period: the epidemiologic data on the insulin resistance syndrome prospective study. , 2004, Diabetes.

[37]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[38]  C. Dina,et al.  Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. , 2000, American journal of human genetics.

[39]  S. Humphries,et al.  Common Adiponectin Gene Variants Show Different Effects on Risk of Cardiovascular Disease and Type 2 Diabetes in European Subjects , 2007, Annals of human genetics.

[40]  Gerome Breen,et al.  Genetic Variation , 2020, Population Genetics with R.

[41]  T. Quertermous,et al.  Genetic epistasis of adiponectin and PPARγ2 genotypes in modulation of insulin sensitivity: a family-based association study , 2003, Diabetologia.

[42]  J. Manson,et al.  Genetic variation at the adiponectin locus and risk of type 2 diabetes in women. , 2004, Diabetes.

[43]  Subhajyoti De,et al.  Common variants near MC4R are associated with fat mass, weight and risk of obesity , 2008, Nature Genetics.

[44]  K. Humphreys,et al.  Single nucleotide polymorphisms in the proximal promoter region of the adiponectin (APM1) gene are associated with type 2 diabetes in Swedish caucasians. , 2004, Diabetes.

[45]  Donald W. Bowden,et al.  Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study , 2005, Human Genetics.

[46]  S. Hanazawa,et al.  Adiponectin inhibits Toll‐like receptor family‐induced signaling , 2005, FEBS letters.

[47]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[48]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[49]  Claude Bouchard,et al.  Mutations in the adiponectin gene in lean and obese subjects from the Swedish obese subjects cohort. , 2003, Metabolism: clinical and experimental.

[50]  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.

[51]  K. Kotani,et al.  Adiponectin I164T gene polymorphism and the obesity-related effects on the Japanese female population. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[52]  W. Hul,et al.  Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children , 2006, International Journal of Obesity.

[53]  H. Motoshima,et al.  Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. , 2003, Diabetes.

[54]  Michael Knapp,et al.  Maximum‐likelihood estimation of haplotype frequencies in nuclear families , 2004, Genetic epidemiology.

[55]  J. Nishioka,et al.  Adiponectin gene variation associates with the increasing risk of type 2 diabetes in non-diabetic Japanese subjects. , 2005, International journal of molecular medicine.

[56]  M. Górska,et al.  Single Nucleotide Polymorphisms in exon 3 of the adiponectin gene in subjects with type 2 diabetes mellitus. , 2005, Roczniki Akademii Medycznej w Bialymstoku.

[57]  F. Kronenberg,et al.  Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1,727 healthy Caucasians. , 2006, Diabetes.

[58]  J. H. Lee,et al.  Association of the 276G->T polymorphism of the adiponectin gene with cardiovascular disease risk factors in nondiabetic Koreans. , 2005, The American journal of clinical nutrition.

[59]  I. Vauhkonen,et al.  Association of adiponectin level and variants in the adiponectin gene with glucose metabolism, energy expenditure, and cytokines in offspring of type 2 diabetic patients. , 2005, The Journal of clinical endocrinology and metabolism.

[60]  S. O’Rahilly,et al.  Induction of Adipocyte Complement-related Protein of 30 Kilodaltons by Ppar␥ Agonists: a Potential Mechanism of Insulin Sensitization , 2022 .

[61]  T Nakamura,et al.  An Adipocyte-Derived Plasma Protein, Adiponectin, Adheres to Injured Vascular Walls , 2000, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[62]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[63]  M. Matsuda,et al.  PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. , 2001, Diabetes.

[64]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[65]  J. Després,et al.  Impact of adiponectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men Published, JLR Papers in Press, November 16, 2004. DOI 10.1194/jlr.M400135-JLR200 , 2005, Journal of Lipid Research.

[66]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[67]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[68]  H. Tilg,et al.  Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. , 2004, Biochemical and biophysical research communications.

[69]  Béatrice Jouret,et al.  ACDC/adiponectin polymorphisms are associated with severe childhood and adult obesity. , 2006, Diabetes.

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