The Association Between the Peroxisome Proliferator-Activated Receptor-γ2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE Review and Meta-Analysis

The peroxisome proliferator-activated receptor-γ gene (PPARG) has been implicated in the etiology of type 2 diabetes mellitus and has been investigated in numerous epidemiologic studies. In this Human Genome Epidemiology review, the authors assessed this relation in an updated meta-analysis of 60 association studies. Electronic literature searches were conducted on September 14, 2009. Population-based cohort, case-control, cross-sectional, or genome-wide association studies reporting associations between the PPARG Pro12Ala gene variant (rs1801282) and type 2 diabetes were included. An updated literature-based meta-analysis involving 32,849 type 2 diabetes cases and 47,456 controls in relation to the PPARG Pro12Ala variant was conducted. The combined overall odds ratio, calculated by per-allele genetic model random-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, was 0.86 (95% confidence interval: 0.81, 0.90). The analysis indicated a moderate level of heterogeneity attributable to genuine variation in gene effect size (I2 = 37%). This may reflect the variation observed between ethnic populations and/or differences in body mass index. Work on PPARG Pro12Ala should now focus on the observed heterogeneity in the magnitude of the association between populations. Further investigations into gene-gene and gene-environment interactions may prove enlightening.

[1]  K. Frazer,et al.  Human genetic variation and its contribution to complex traits , 2009, Nature Reviews Genetics.

[2]  Julian Little,et al.  Systematic Reviews of Genetic Association Studies , 2009, PLoS medicine.

[3]  M. McCarthy,et al.  Casting a wider net for diabetes susceptibility genes , 2008, Nature Genetics.

[4]  B. Dallapiccola,et al.  Interaction Between PPARγ2 Variants and Gender on the Modulation of Body Weight , 2008, Obesity.

[5]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[6]  I. Deary,et al.  PPARG Pro12Ala genotype and risk of cognitive decline in elders? Maybe with diabetes , 2008, Neuroscience Letters.

[7]  Siobhan M. Dolan,et al.  Assessment of cumulative evidence on genetic associations: interim guidelines. , 2008, International journal of epidemiology.

[8]  Robert L Hanson,et al.  A Search for Variants Associated With Young-Onset Type 2 Diabetes in American Indians in a 100K Genotyping Array , 2007, Diabetes.

[9]  E. Zeggini,et al.  A new era for Type 2 diabetes genetics , 2007, Diabetic medicine : a journal of the British Diabetic Association.

[10]  Jun Ren,et al.  GENETIC POLYMORPHISM OF PEROXISOME PROLIFERATOR‐ACTIVATED RECEPTOR‐γ2 PRO12ALA ON ETHNIC SUSCEPTIBILITY TO DIABETES IN UYGUR, KAZAK AND HAN SUBJECTS , 2007, Clinical and experimental pharmacology & physiology.

[11]  T. Frayling.  Genome–wide association studies provide new insights into type 2 diabetes aetiology , 2007, Nature Reviews Genetics.

[12]  M. Hutz,et al.  Effects of a PPARG gene variant on obesity characteristics in Brazil. , 2007, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[13]  A. Minenna,et al.  Heterogeneous Effect of Peroxisome Proliferator‐activated Receptor γ2 Ala12 Variant on Type 2 Diabetes Risk , 2007, Obesity.

[14]  C. Craig,et al.  Adiposity, physical fitness and incident diabetes: the physical activity longitudinal study , 2007, Diabetologia.

[15]  B. Spiegelman,et al.  International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors , 2006, Pharmacological Reviews.

[16]  Roger M Harbord,et al.  A modified test for small‐study effects in meta‐analyses of controlled trials with binary endpoints , 2006, Statistics in medicine.

[17]  R. Cox,et al.  Type-2 diabetes: a cocktail of genetic discovery. , 2006, Human molecular genetics.

[18]  E. Taioli,et al.  Genetics of leptin and obesity: a HuGE review. , 2005, American journal of epidemiology.

[19]  E. Ruiz-Narváez,et al.  Is the Ala12 variant of the PPARG gene an “unthrifty allele”? , 2005, Journal of Medical Genetics.

[20]  K. Clément,et al.  Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population , 2005, BMC Medical Genetics.

[21]  J. Auwerx,et al.  Peroxisome proliferator‐activated receptor γ: the more the merrier? , 2005, European journal of clinical investigation.

[22]  Keith R Abrams,et al.  An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization. , 2004, American journal of epidemiology.

[23]  L. Groop,et al.  Candidate Genes for Type 2 Diabetes , 2004, Reviews in Endocrine and Metabolic Disorders.

[24]  S. Wild,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[25]  Mark I McCarthy,et al.  Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification. , 2004, Human molecular genetics.

[26]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[27]  Karim Benkirane,et al.  Vascular and Cardiac Effects in Hypertension , 2022 .

[28]  L. Cherkas,et al.  Effect of the peroxisome proliferator activated receptor-γ gene Pro12Ala variant on body mass index: a meta-analysis , 2003, Journal of medical genetics.

[29]  T. Kadowaki,et al.  [The role of PPARgamma in the onset of type 2 diabetes]. , 2003, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[30]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[31]  A. Gloyn.  The search for type 2 diabetes genes , 2003, Ageing Research Reviews.

[32]  P. McKeigue,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Problems of Reporting Genetic Associations with Complex Outcomes , 2022 .

[33]  Thomas A Trikalinos,et al.  Genetic associations in large versus small studies: an empirical assessment , 2003, The Lancet.

[34]  L. Pérusse,et al.  The PPAR‐gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: results from the Québec Family Study , 2003, Clinical genetics.

[35]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[36]  J. Auwerx,et al.  Role of peroxisome proliferator-activated receptor γ and retinoid X receptor heterodimer in hepatogastroenterological diseases , 2002, The Lancet.

[37]  J. Shaw,et al.  Global and societal implications of the diabetes epidemic , 2001, Nature.

[38]  T. Hansen,et al.  Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene in relation to insulin sensitivity among glucose tolerant Caucasians , 2001, Diabetologia.

[39]  S. O’Rahilly,et al.  Evidence for Gene-Nutrient Interaction at the PPARγ Locus , 2001 .

[40]  L. Chuang,et al.  Peroxisome proliferator-activated receptor gamma 2 Pro12Ala gene variant is strongly associated with larger body mass in the Taiwanese. , 2000, Metabolism: clinical and experimental.

[41]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[42]  R. A. Price,et al.  The Peroxisome Proliferator-Activated Receptor γ2 Pro12Ala Mutation Is Associated with Early Onset Extreme Obesity and Reduced Fasting Glucose , 2000 .

[43]  M. Kasuga,et al.  Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. , 2000, Biochemical and biophysical research communications.

[44]  N. Day,et al.  EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. , 1999, British journal of cancer.

[45]  C. Day.  Thiazolidinediones: a new class of antidiabetic drugs , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[46]  Johan Auwerx,et al.  A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity , 1998, Nature Genetics.

[47]  P. Zimmet,et al.  The thrifty genotype in type 2 diabetes , 1998, Endocrine.

[48]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[49]  Uk-Prospective-Diabetes-Study-Group.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) , 1998, The Lancet.

[50]  B. Spiegelman.  PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. , 1998, Diabetes.

[51]  K. Silver,et al.  Molecular Scanning of the Human Peroxisome Proliferator Activated Receptor γ (hPPARγ) Gene in Diabetic Caucasians: Identification of a Pro12Ala PPARγ2 Missense Mutation , 1997 .

[52]  J. Flier,et al.  Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. , 1997, The Journal of biological chemistry.

[53]  J. Auwerx,et al.  The Organization, Promoter Analysis, and Expression of the Human PPARγ Gene* , 1997, The Journal of Biological Chemistry.

[54]  J. Paterniti,et al.  Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists* , 1997, The Journal of Biological Chemistry.

[55]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[56]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[57]  J. Neel.  Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? , 1962, American journal of human genetics.

[58]  E. Cerasi,et al.  DIABETES MELLITUS , 1924, Nihon rinsho. Japanese journal of clinical medicine.