The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes

Clément, Karine; Herçberg, Serge; Passinge, B; Galán, Pilar; Varroud-Vial, Michel; Shuldiner, AR; Beamer, BA; Charpentier, G.; Guy‐Grand, Bernard; Froguel, Philippe; Vaisse, Christian

doi:10.1038/sj.ijo.0801191

Cited by 127 publications

(94 citation statements)

References 18 publications

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“…In contrast to ACDC promoter SNPs, the PPARG Pro12Ala SNP only displayed a trend of association with type 2 diabetes in the non-obese group; an association with type 2 diabetes in obese groups failed to be demonstrated [31]. The OR found here in non-obese and obese groups (1.40 and 1.39, respectively) are in the same range as those previously reported in other populations [14].…”

Section: Discussionsupporting

confidence: 78%

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

et al. 2005

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Aims/hypothesis: Morbid obesity (BMI>40 kg/ m 2 ) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. Methods: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagendomain-containing (ACDC) gene (−11,391G>A, −11,377C> G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6±7.4 kg/m 2 ), 808 non-obese subjects (BMI<30 kg/m 2 ) and 493 obese subjects (30≤BMI<40 kg/m 2 ). Results: Two 5′-ACDC SNPs −11,391G>A, −11,377C>G were associated with adiponectin levels (p=0.0003, p= 0.008) and defined a 'low-level' haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5′-ACDC 'low-level' haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals.Conclusions/interpretation: These data clarify the contribution of the 5′-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.

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Section: Discussionsupporting

confidence: 78%

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

et al. 2005

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“…Kao et al (12) showed variations in BMI and fasting insulin depending on Pro12Ala genotype (P¼0·0027). Two other studies showed lower obesity levels associated with insulin genotype Pro12Pro (33,34) , but there was no apparent similarity between the studies that had shifted to the right on the graph of this analysis.…”

Section: Discussionmentioning

confidence: 70%

The Ala allele in the PPAR-γ2 gene is associated with reduced risk of type 2 diabetes mellitus in Caucasians and improved insulin sensitivity in overweight subjects

Huguenin

Rosa

2010

Br J Nutr

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The purpose of the present study was to identify the association of the Pro12Ala polymorphism in the PPAR-g2 gene with diabetes, insulinaemia and insulin resistance. A meta-analysis study was carried out based on studies conducted in the last 10 years, using the databases PubMed, ISI Web of Knowledge, High Wire Press and Scielo, and the reference lists of the obtained articles. We included original studies that showed the relationship between the Pro12Ala polymorphism in the PPAR-g2 gene and type 2 diabetes mellitus (T2DM), insulinaemia and insulin resistance. Statistical analyses were conducted using the program RevMAn 5.0. The Mantel -Haenszel test was used to estimate the OR and the 95 % CI of the dichotomous variable, while the standardised effect size was used to estimate the average standardised mean difference and 95 % CI of continuous variables. The studies were subgrouped by ethnicity and overweight status. Forty-one studies were analysed, including a global sample of 30 612 subjects. We found a significant association of the Ala allele with the lowest risk of T2DM in Caucasians (OR 0·80; 95 % CI 0·65, 0·98), lower serum insulin (standardised effect size: 2 0·05; 95 % CI 20·09, 2 0·00; P¼0·04), and greater sensitivity to insulin in overweight individuals (homeostasis model assessment of insulin resistance standardised effect size: 20·07; 95 % CI 2 0·13, 2 0·01; P¼ 0·02). Considering that the Pro12Ala polymorphism in the PPAR-g2 gene is one of the factors related to insulin sensitivity, the present study demonstrated a significant effect of the Ala allele on lower development of T2DM in Caucasians and greater sensitivity to insulin in overweight subjects.

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“…In vitro studies showed that this allele reduces PPARg DNA binding affinity and transcriptional activity [70,73,194,195]. Although some additional studies did not support a statistically significant role for the PPARg 2 P12A polymorphism in the etiology of type 2 diabetes [196][197][198], a more recent meta-analysis of all published data, comprising more than 25 000 cases of diabetes, showed an association of P12A with type 2 diabetes [199]. The large population that was necessary in order to demonstrate the association between P12A and type 2 diabetes is due to the weak effect of the risk allele, since individuals that are homozygous for the higher risk P12 allele have only a 25% increase in diabetes risk.…”

Section: Pparg Loss Of Function Mutationsmentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes

Cited by 127 publications

References 18 publications

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

The Ala allele in the PPAR-γ2 gene is associated with reduced risk of type 2 diabetes mellitus in Caucasians and improved insulin sensitivity in overweight subjects

Fat poetry: a kingdom for PPARγ

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