Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women.

We assessed the association of four polymorphisms (promoter P3 -681C>G, P2 -689C>T, Pro12Ala, and 1431C>T) in peroxisome proliferator-activated receptor gamma (PPARgamma) with the metabolic syndrome risk in a large, French population study (n = 1,155). In this sample, 279 men and women presented with metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. When taken individually, none of the polymorphisms was significantly associated with the metabolic syndrome. Haplotype analyses, in contrast, revealed a significant enrichment of the GTGC haplotype frequency (corresponding to the P3 -681C>G, P2 -689C>T, Pro12Ala (C/G), and 1431C>T polymorphisms in this order) among those with metabolic syndrome compared with control subjects. Compared with the most common CCCC haplotype, the adjusted odds ratio (OR) (95% CI) of the metabolic syndrome for bearers of the GTGC haplotype was 2.37 (1.42-3.95; P = 0.002), 1.92 (1.00-3.72; P = 0.05), and 2.47 (1.09-5.62; P = 0.045) in the whole sample of men and women, respectively. Similar results were obtained when using another haplotype (GCCC, GTGT, CCCT, or GCCT) as a reference. Furthermore, when the GTGC haplotype frequency was tested alone (i.e., versus the frequency of the five other haplotypes together), the OR (95% CI) of the metabolic syndrome was 2.30 (1.05-5.00; P = 0.022). These data show that only the frequency of the GTGC haplotype was different between subjects with and without metabolic syndrome. Further analyses stratified on the 1431C>T single nucleotide polymorphism (SNP) indicated that the rare alleles of the P2 -689C>T and Pro12Ala SNPs were associated with an increased risk of the metabolic syndrome when combined to the 1431CC genotype. In conclusion, a specific haplotype of PPARgamma polymorphisms is associated with an increased risk of the metabolic syndrome in a French general population.

[1]  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.

[2]  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.

[3]  D. Aaronson,et al.  A Road Map for Those Who Don't Know JAK-STAT , 2002, Science.

[4]  J. Auwerx,et al.  A Functional Polymorphism in a STAT5B Site of the Human PPAR&ggr;3 Gene Promoter Affects Height and Lipid Metabolism in a French Population , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[5]  J. Chan,et al.  Renin-angiotensin system gene polymorphisms, blood pressure, dyslipidemia, and diabetes in Hong Kong Chinese: a significant association of tne ACE insertion/deletion polymorphism with type 2 diabetes. , 2001, Diabetes care.

[6]  T. Jørgensen,et al.  Studies of the Pro12Ala polymorphism of the ppar-γ gene in the Danish MONICA cohort: Homozygosity of the Ala allele confers a decreased risk of the Insulin Resistance syndrome , 2002 .

[7]  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.

[8]  P. Amouyel,et al.  The Gly16-->Arg16 and Gln27-->Glu27 polymorphisms of beta2-adrenergic receptor are associated with metabolic syndrome in men. , 2003, The Journal of clinical endocrinology and metabolism.

[9]  D. Tregouet,et al.  A new algorithm for haplotype‐based association analysis: the Stochastic‐EM algorithm , 2004, Annals of human genetics.

[10]  G. Heiss,et al.  Familial components of the multiple metabolic syndrome: the ARIC Study , 1997, Diabetologia.

[11]  J. O’Connell,et al.  Variation in the Lamin A/C Gene: Associations With Metabolic Syndrome , 2004, Arteriosclerosis, thrombosis, and vascular biology.

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

[13]  P. Amouyel,et al.  Impact of genetic variation of PPARγ in humans , 2004 .

[14]  J. Auwerx,et al.  Study of a new PPARgamma2 promoter polymorphism and haplotype analysis in a French population. , 2005, Molecular genetics and metabolism.

[15]  B. Balkau,et al.  Comment on the provisional report from the WHO consultation , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[16]  J. Tsai,et al.  ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. , 2002, Diabetes care.

[17]  A. Pfeiffer,et al.  Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. , 1998, The New England journal of medicine.

[18]  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.

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

[20]  Kari Kuulasmaa,et al.  Ecological analysis of the association between mortality and major risk factors of cardiovascular disease. The World Health Organization MONICA Project. , 1994, International journal of epidemiology.

[21]  F. Sestier,et al.  Metabolic syndrome X: a review. , 2000, The Canadian journal of cardiology.

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

[23]  Jean-Louis Golmard,et al.  Specific haplotypes of the P-selectin gene are associated with myocardial infarction. , 2002, Human molecular genetics.

[24]  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.

[25]  J. Mckenney,et al.  Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) , 1993, JAMA.

[26]  Y. Terauchi,et al.  The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor γ (PPARγ) Deficiency and PPARγ Agonist Improve Insulin Resistance* , 2001, The Journal of Biological Chemistry.

[27]  David J. Moliterno,et al.  Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients , 2003, Human Genetics.

[28]  A. Doney,et al.  Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes , 2004, Diabetologia.