Adiponectin and Resistin Gene Polymorphisms in Association with Their Respective Adipokine Levels

Single nucleotide polymorphisms (SNPs) at the adiponectin and resistin loci are strongly associated with hypoadiponectinemia and hyperresistinemia, which may eventually increase risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease. Real‐time PCR was used to genotype SNPs of the adiponectin (SNP+45T>G, SNP+276G>T, SNP+639T>C, and SNP+1212A>G) and resistin (SNP‐420C>G and SNP+299G>A) genes in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40 and 70 years old. The genotyping results for each SNP marker was verified by sequencing. The anthropometric clinical and metabolic parameters of subjects were recorded. None of these SNPs at the adiponectin and resistin loci were associated with T2DM and MS susceptibility in Malaysian men. SNP+45T>G, SNP+276G>T, and SNP+639T>C of the adiponectin gene did not influence circulating levels of adiponectin. However, the G‐allele of SNP+1212A>G at the adiponectin locus was marginally associated (P= 0.0227) with reduced circulating adiponectin levels. SNP‐420C>G (df = 2; F= 16.026; P= 1.50×10−7) and SNP+299G>A (df = 2; F= 22.944; P= 2.04×10−10) of the resistin gene were strongly associated with serum resistin levels. Thus, SNP‐420C>G and SNP+299G>A of the resistin gene are strongly associated with the risk of hyperresistinemia in Malaysian men.

[1]  C. Aguilar-Salinas,et al.  Cardio Vascular Diabetology Open Access Original Investigation Total and High Molecular Weight Adiponectin Have Similar Utility for the Identification of Insulin Resistance , 2022 .

[2]  R. Dullaart,et al.  Do genome-wide association scans provide additional information on the variation of plasma adiponectin concentrations? , 2010, Atherosclerosis.

[3]  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.

[4]  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.

[5]  E. Ding,et al.  Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. , 2009, JAMA.

[6]  S. Grundy,et al.  Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International As , 2009, Circulation.

[7]  E. Rimm,et al.  The +276 polymorphism of the APM1 gene, plasma adiponectin concentration, and cardiovascular risk in diabetic men. , 2005, Diabetes.

[8]  Kazuya Yamada,et al.  The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. , 2004, American journal of human genetics.

[9]  J. Blangero,et al.  Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon , 2008, Heredity.

[10]  Marek Kimmel,et al.  Simulations Provide Support for the Common Disease–Common Variant Hypothesis , 2007, Genetics.

[11]  H. K. Lee,et al.  Erratum to: Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans , 2004, Diabetologia.

[12]  Y. M. Cho,et al.  Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans , 2004, Diabetologia.

[13]  Y. M. Cho,et al.  Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site , 2005, Diabetologia.

[14]  C. Langefeld,et al.  Coincident Linkage of Type 2 Diabetes, Metabolic Syndrome, and Measures of Cardiovascular Disease in a Genome Scan of the Diabetes Heart Study , 2006, Diabetes.

[15]  J. Whitehead,et al.  Adiponectin--it's all about the modifications. , 2010, The international journal of biochemistry & cell biology.

[16]  H. Izawa,et al.  Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population , 2010, Diabetologia.

[17]  J. Hwang,et al.  SNP276G>T polymorphism in the adiponectin gene is associated with metabolic syndrome in patients with Type II diabetes mellitus in Korea , 2010, European Journal of Clinical Nutrition.

[18]  C. Fox,et al.  Common Variants in the Adiponectin Gene (ADIPOQ) Associated With Plasma Adiponectin Levels, Type 2 Diabetes, and Diabetes-Related Quantitative Traits , 2008, Diabetes.

[19]  R. Nussbaum,et al.  Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones , 2022 .

[20]  S. Lillioja,et al.  Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies , 2009, Diabetologia.

[21]  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.

[22]  M. J. Vazquez,et al.  Resistin: regulation of food intake, glucose homeostasis and lipid metabolism. , 2010, Endocrine development.

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

[24]  J. Skupień,et al.  Variants of the adiponectin gene and type 2 diabetes in a Polish population , 2009, Acta Diabetologica.

[25]  H. Gu.  Biomarkers of Adiponectin: Plasma Protein Variation and Genomic DNA Polymorphisms , 2009, Biomarker insights.

[26]  Charles Rotimi,et al.  A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans , 2009, PLoS genetics.

[27]  Fuu-Jen Tsai,et al.  A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese , 2010, PLoS genetics.

[28]  J. Stockman.  Adiponectin Levels and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis , 2011 .

[29]  M. Laakso,et al.  Common polymorphisms (single-nucleotide polymorphisms SNP+45 and SNP+276) of the adiponectin gene regulate serum adiponectin concentrations and blood pressure in young Finnish men. , 2006, Molecular genetics and metabolism.

[30]  I. Ntalla,et al.  ADIPOQ gene polymorphism rs1501299 interacts with fibre intake to affect adiponectin concentration in children: the GENe–Diet Attica Investigation on childhood obesity , 2009, European journal of nutrition.

[31]  C. Kusminski,et al.  The Road From Discovery to Clinic: Adiponectin as a Biomarker of Metabolic Status , 2009, Clinical pharmacology and therapeutics.

[32]  A. Doria,et al.  Heritability of serum resistin and its genetic correlation with insulin resistance-related features in nondiabetic Caucasians. , 2006, The Journal of clinical endocrinology and metabolism.

[33]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[34]  Y. Kokubo,et al.  Identification of genetic markers associated with high-density lipoprotein-cholesterol by genome-wide screening in a Japanese population: the Suita study. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[35]  N. Kato,et al.  Polymorphism in resistin promoter region at -420 determines the serum resistin levels and may be a risk marker of stroke in Japanese type 2 diabetic patients. , 2009, Diabetes research and clinical practice.

[36]  Toshiko Tanaka,et al.  A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels , 2009, PLoS genetics.

[37]  T. Wong,et al.  Polymorphisms Identified through Genome-Wide Association Studies and Their Associations with Type 2 Diabetes in Chinese, Malays, and Asian-Indians in Singapore. , 2009, Endocrine reviews.

[38]  Xiao-guang Yang,et al.  Association between adiponectin and metabolic syndrome in older adults from major cities of China. , 2010, Biomedical and environmental sciences : BES.

[39]  Christian Gieger,et al.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk , 2010, Nature Genetics.

[40]  D. Balding,et al.  A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men , 2010, PloS one.

[41]  Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore. , 2010, The Journal of clinical endocrinology and metabolism.

[42]  A. Doria,et al.  Genetic Influences of Adiponectin on Insulin Resistance, Type 2 Diabetes, and Cardiovascular Disease , 2007, Diabetes.

[43]  M. Kasuga,et al.  Frequency of the G/G Genotype of Resistin Single Nucleotide Polymorphism at −420 Appears to Be Increased in Younger-Onset Type 2 Diabetes , 2007, Diabetes.

[44]  H. Putter,et al.  Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions , 2005, European Journal of Human Genetics.

[45]  Y. Kokubo,et al.  Resistin gene variations are associated with the metabolic syndrome in Japanese men. , 2009, Obesity research & clinical practice.

[46]  Y. Tabara,et al.  Is rs34861192 or rs1862513 a more promising variant for determining plasma resistin in an aged Japanese population? , 2010, Diabetologia.

[47]  R. Tungtrongchitr,et al.  The +299(G>A) Resistin Gene Polymorphism and Susceptibility to Type 2 Diabetes in Thais , 2008, Journal of clinical biochemistry and nutrition.

[48]  C. Langefeld,et al.  Association of Adiponectin Gene Polymorphisms With Type 2 Diabetes in an African American Population Enriched for Nephropathy , 2009, Diabetes.

[49]  P. O S I T I O N S T A T E M E N T,et al.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[50]  David M. Evans,et al.  Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals. , 2010, Atherosclerosis.

[51]  Paul Zimmet,et al.  The metabolic syndrome—a new worldwide definition , 2005, The Lancet.

[52]  Y. Tabara,et al.  A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes. , 2009, Endocrine journal.

[53]  Lin He,et al.  SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci , 2005, Cell Research.

[54]  C. V. van Duijn,et al.  Genetic Architecture of Plasma Adiponectin Overlaps With the Genetics of Metabolic Syndrome–Related Traits , 2010, Diabetes Care.

[55]  Yun Liu,et al.  Association study of the single nucleotide polymorphisms in adiponectin-associated genes with type 2 diabetes in Han Chinese. , 2009, Journal of genetics and genomics = Yi chuan xue bao.

[56]  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.

[57]  K. Taylor,et al.  Genome-Wide Association , 2007, Diabetes.

[58]  Reiko Ohmori,et al.  Serum resistin levels and cardiovascular events in patients undergoing percutaneous coronary intervention. , 2011, Journal of atherosclerosis and thrombosis.

[59]  J. Pankow,et al.  Variants in the Adiponectin Gene and Serum Adiponectin: The Coronary Artery Development in Young Adults (CARDIA) Study , 2010, Obesity.

[60]  K. Kohara,et al.  A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population , 2010, PloS one.

[61]  C. Rotimi,et al.  Meta-Analysis of Genome-Wide Linkage Studies of Quantitative Lipid Traits in Families Ascertained for Type 2 Diabetes , 2007, Diabetes.

[62]  Brian H Chen,et al.  Circulating Levels of Resistin and Risk of Type 2 Diabetes in Men and Women: Results From Two Prospective Cohorts , 2009, Diabetes Care.

[63]  Yves Moreau,et al.  Detection of novel 3' untranslated region extensions with 3' expression microarrays , 2010, BMC Genomics.

[64]  C. Hutter,et al.  Genome‐wide Linkage Scan for the Metabolic Syndrome: The GENNID Study , 2008, Obesity.

[65]  Y. Kesäniemi,et al.  Genetic variants at the resistin locus are associated with the plasma resistin concentration and cardiovascular risk factors , 2008, Regulatory Peptides.

[66]  J. Pankow,et al.  Suggestion for linkage of chromosome 1p35.2 and 3q28 to plasma adiponectin concentrations in the GOLDN Study , 2009, BMC Medical Genetics.

[67]  P. Sham,et al.  Association of genetic variants in the adiponectin gene with adiponectin level and hypertension in Hong Kong Chinese. , 2010, European journal of endocrinology.

[68]  T. Beaty,et al.  Adiponectin concentrations: a genome-wide association study. , 2010, American journal of human genetics.

[69]  V. Trischitta,et al.  Genetics of serum resistin: a paradigm of population-specific regulation? , 2010, Diabetologia.

[70]  Y. Kokubo,et al.  A genome-wide association study of hypertension-related phenotypes in a Japanese population. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[71]  G. Steinberg,et al.  Adipose tissue as an endocrine organ , 2010, Molecular and Cellular Endocrinology.

[72]  C. Fox,et al.  Association of Variants in RETN With Plasma Resistin Levels and Diabetes-Related Traits in the Framingham Offspring Study , 2009, Diabetes.

[73]  S. Wild,et al.  The TCF7L2 Diabetes Risk Variant is Associated with HbA1C Levels: a Genome‐Wide Association Meta‐Analysis , 2010, Annals of human genetics.

[74]  A. Doria,et al.  Circulating high molecular weight adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family‐based study , 2010, Journal of internal medicine.

[75]  A. Pereira,et al.  Association of genetic variants in the adiponectin encoding gene (ADIPOQ) with type 2 diabetes in Japanese Brazilians. , 2010, Journal of diabetes and its complications.