Differential effects of the C1431T and Pro12Ala PPARγ gene variants on plasma lipids and diabetes risk in an Asian population Published, JLR Papers in Press, January 16, 2004. DOI 10.1194/jlr.M300363-JLR200

We investigated the association of C1431T and Pro12Ala polymorphisms at the peroxisome proliferator-activated receptor γ (PPARγ) locus with plasma lipids and insulin resistance-related variables, according to diabetes status, in a large and representative Asian population from Singapore consisting of 2,730 Chinese, 740 Malays, and 568 Indians. Moreover, we estimated the diabetes risk and examined gene-nutrient interactions between these variants and the ratio of polyunsaturated fatty acid to saturated fat (SFA) in determining body mass index (BMI) and fasting insulin. We found differential effects of these gene variants. The Pro12Ala polymorphism was more associated with plasma lipids and fasting glucose concentrations, whereas the C1431T polymorphism was related to the risk of diabetes. Carriers of the 12Ala allele had higher HDL-cholesterol than did Pro12Pro homozygotes (P < 0.05), and the effect of the 12Ala allele on fasting glucose was modified by diabetes status (P < 0.001). After controlling for confounders, carriers of the T allele had decreased risk of diabetes compared with CC homozygotes [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58–0.93; P = 0.011]; this effect was stronger in Indians (OR 0.38, 95% CI 0.15–0.92; P = 0.032). For both polymorphisms, normal subjects carrying the less prevalent allele had higher BMI (P < 0.05). The PUFA/SFA did not modify the effect of these polymorphisms on BMI or insulin.

[1]  C. Bogardus,et al.  A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. , 2003, Diabetes.

[2]  S. O’Rahilly,et al.  The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor γ and Its Therapeutic Modulation , 2003 .

[3]  Jimmy D Bell,et al.  Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. , 2003, Diabetes.

[4]  M. Laakso,et al.  Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue of massively obese subjects. , 2003, The Journal of clinical endocrinology and metabolism.

[5]  T. Hayakawa,et al.  PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. , 2003, Metabolism: clinical and experimental.

[6]  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.

[7]  X. Adiconis,et al.  The TaqIB and −629C>A polymorphisms at the cholesteryl ester transfer protein locus: associations with lipid levels in a multiethnic population. The 1998 Singapore National Health Survey , 2002, Clinical genetics.

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

[9]  Allan Vaag,et al.  Impact of two common polymorphisms in the PPARgamma gene on glucose tolerance and plasma insulin profiles in monozygotic and dizygotic twins: thrifty genotype, thrifty phenotype, or both? , 2003, Diabetes.

[10]  A. Morris,et al.  Haplotype analysis of the PPARγ Pro12Ala and C1431T variants reveals opposing associations with body weight , 2002, BMC Genetics.

[11]  M. Laakso,et al.  Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. , 2002, European journal of endocrinology.

[12]  V. Colantuoni,et al.  Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator‐activated receptor (PPAR) γ2 gene in healthy individuals , 2002, Clinical endocrinology.

[13]  C. Weinberg,et al.  Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. , 2002, American journal of epidemiology.

[14]  J. Schölmerich,et al.  Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) is associated with higher levels of total cholesterol and LDL-cholesterol in male caucasian type 2 diabetes patients. , 2002, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[15]  T. Jørgensen,et al.  Comment: studies of the Pro12Ala polymorphism of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the Ala allele confers a decreased risk of the insulin resistance syndrome. , 2002, The Journal of clinical endocrinology and metabolism.

[16]  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.

[17]  F. Collins,et al.  The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences. , 2001, Diabetes.

[18]  M. Kasuga,et al.  The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. , 2001, Diabetes.

[19]  S. O’Rahilly,et al.  Evidence for gene-nutrient interaction at the PPARgamma locus. , 2001, Diabetes.

[20]  J. Beilby,et al.  A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-gamma 2 is associated with combined hyperlipidaemia in obesity. , 2001, European journal of endocrinology.

[21]  P. Deurenberg,et al.  Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore? , 2001, Asia Pacific journal of clinical nutrition.

[22]  D. Cox,et al.  Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance. , 2001, Journal of molecular medicine.

[23]  U. Beisiegel,et al.  Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. , 2001, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[24]  S. Lien,et al.  Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. , 2001, Biochemical and biophysical research communications.

[25]  S. Chew,et al.  Levels of cardiovascular disease risk factors in Singapore following a national intervention programme. , 2001, Bulletin of the World Health Organization.

[26]  P. Deurenberg,et al.  Validation of a semiquantitative food frequency questionnaire for estimation of intakes of energy, fats and cholesterol among Singaporeans. , 2000, Asia Pacific journal of clinical nutrition.

[27]  L. Tiret,et al.  The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ2 gene is not associated with postprandial responses to glucose or fat tolerance tests in young healthy subjects: the European Atherosclerosis Research Study II , 2000, Journal of Molecular Medicine.

[28]  Y. Min,et al.  Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. , 2000, The Journal of clinical endocrinology and metabolism.

[29]  K. Clément,et al.  The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes , 2000, International Journal of Obesity.

[30]  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.

[31]  J. Auwerx,et al.  Impact of the Peroxisome Proliferator Activated Receptor γ2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus , 2000, International Journal of Obesity.

[32]  T. Kadowaki,et al.  The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. , 2000, Biochemical and biophysical research communications.

[33]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[34]  M. Laakso,et al.  Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated with severe overweight among obese women. , 1999, The Journal of clinical endocrinology and metabolism.

[35]  V. Colantuoni,et al.  Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. , 1999, Diabetes.

[36]  H. Häring,et al.  The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects , 1999, Diabetologia.

[37]  S. Engeli,et al.  Pro12Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. , 1999, Biochemical and biophysical research communications.

[38]  X. L. Wang,et al.  Peroxisome proliferator-activated receptor gamma C161-->T polymorphism and coronary artery disease. , 1999, Cardiovascular research.

[39]  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.

[40]  C. Yen,et al.  Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. , 1998, Diabetes.

[41]  G. Gyapay,et al.  Human peroxisome proliferator-activated receptor-gamma2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. , 1998, Diabetes.

[42]  J. Auwerx,et al.  A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. , 1998, Human molecular genetics.

[43]  J. Auwerx,et al.  PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. , 1998, FEBS letters.

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

[45]  K. Silver,et al.  Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. , 1997, Biochemical and biophysical research communications.

[46]  M. Fantone,et al.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus , 1997, Diabetes Care.

[47]  J Auwerx,et al.  Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. , 1996, Journal of lipid research.