PPARγ Gene Polymorphisms Research Articles

Association of the PPARγ gene polymorphism Pro12Ala with delayed onset of multiple sclerosis

PPARs belong to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. A crucial role both for PPARγ and for PPARα for the regulation of autoimmunity has been clearly demonstrated, as receptor agonists had beneficial effects on several CD4 + T cell mediated autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. We investigated the association of two common single nucleotide polymorphisms in the PPARA (Leu162Val) and the PPARG (Pro12Ala) genes in 116 patients with clinically definite multiple sclerosis (MS) and 211 age-matched healthy controls. The Ala allele of the PPARG Pro12Ala polymorphism was strongly associated with delayed disease onset (44.1 ± 5.3 years vs 34.5 ± 4.2 years; p = 0.006). No significant differences were found in genotype distributions and allele frequencies of the PPARA Leu162Val and the PPARG Pro12Ala polymorphisms between MS patients and healthy controls, respectively. Our population-based study demonstrates that the Pro12Ala polymorphism resulting in an amino acid exchange in the N-terminal sequence of PPARγ may influence the onset of MS.

Peroxisome Proliferator-Activated Receptor-Gamma Gene Polymorphism and Risk of Cardiovascular Disease in Patients with Diabetic Nephropathy

Background: Peroxisome proliferator-activator receptor-gamma (PPAR-γ) is a nuclear receptor that serves important roles in intermediate metabolism. We examined the relationship between two PPAR-γ gene polymorphisms, namely the P12A and C161T, and cardiovascular disease in patients with diabetic nephropathy. Methods: We studied 170 predialysis and 50 peritoneal dialysis patients with diabetic nephropathy. The PPAR-γ genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assay. The patients were then followed prospectively for the development of cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. Results: There were 91 male cases. The mean age was 64.3 ± 10.6 years. The frequencies of Pro/Pro and Pro/Ala genotypes of the P12A polymorphism were 95 and 5%, respectively; CC, CT and TT genotypes of the C161T polymorphism were 55.5, 39.5 and 5.0%, respectively. For the P12A polymorphism, the event-free survival was 56.5 and 9.1% at 60 months for Pro/Pro and Pro/Ala genotypes, respectively (p = 0.0005). For the C161T polymorphism, the event-free survival was 61.5 and 44.9% for CC and CT/TT genotypes, respectively (p = 0.0044). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the independent factors for event-free survival were P12A and C161T polymorphisms, age and diastolic blood pressure. In this model, the Pro/Ala genotype conferred 7.6-fold (95% CI 2.1- to 28.0-fold, p = 0.002) excess hazard of developing primary cardiovascular end point as compared to the Pro/Pro genotype, while each T allele at the 161 position conferred 83.4% (95% CI 15.2–291.9%, p = 0.011) excess hazard. Conclusions: We conclude that P12A and C161T polymorphisms of the PPAR-γ gene are important predictors of cardiovascular event in patients with diabetic nephropathy. Further studies are needed to examine the interaction of PPAR-γ gene polymorphisms and thiazolidinedione treatment on the cardiovascular risk in this group of patients.

PPARs/RXRs in Cardiovascular Physiology and Disease

The PPAR family of nuclear receptor transcription factors are important regulators of cardiovascular function and metabolism. Because of this, PPARs are potentially interesting pharmacologic targets for treating cardiometabolic disease. The reviews in this series discuss the regulatory functions of PPARs in maintaining metabolic and physiologic homeostasis in a variety of cells and tissues. Additionally, the therapeutic potential and mechanisms of action of ligands of the different PPAR isotypes are discussed. The review series is started by an examination of the effects of PPARs on lipoprotein metabolism. This is one of the first identified functions of PPARs. Indeed, ligands for PPARα were in clinical use as lipid-lowering agents even before their pharmacological target, PPARα, were known. The second review evaluates the important anti-inflammatory effects of PPARs in platelets, which is emerging as an important mechanism of their beneficial effects. Next, the critical role that PPARα and its transcriptional coactivator protein PGC-1α play in regulating energy metabolism and function of the myocardium is discussed. Then, a series of reviews focuses on the potentially beneficial effects of PPARγ agonists on the cardiovascular system. Several aspects are presented. The effects of PPAR activation on the cardiovascular system as a whole, on the vascular smooth muscle cell, and in the context of diabetic cardiovascular disease are each discussed at length. A review by Demers et al. also discusses the potential input of the hexarelin signaling pathway in regulating PPARγ activity and its potential impact on cardiometabolic disease. The genes encoding the PPARs are rich with genetic variation and the impact of these polymorphisms and haplotypes on the response to PPAR activators is only beginning to be understood. Thus, the “pharmacogenomics” of PPARs are discussed in a review by Dr. Sharon Cresci. Finally, the potential toxicity and adverse outcomes of PPAR agonism are summarized in detail by Jennifer Robinson. The timeliness of this discussion is outstanding given the recent reports of increased cardiovascular morbidity associated with use of rosiglitazone and the failure of PPAR dual agonists at different stages of development. Several of the other reviews in this series also touch this controversial issue at least briefly. We are also pleased to present two original research reports. The first report found associations between PPARγ gene polymorphisms and several cardiometabolic indices, but found no link with cardiovascular morbidity and mortality. Second, Buroker et al. report an important role for PGC- 1α in postnatal metabolic maturation. This preprogrammed burst in cardiac oxidative metabolism is an important developmental response that also has implications for other physiologic states wherein the demand for ATP production is rapidly induced. We hope that you will find this issue enjoyable and informative. Brian N. Finck Giulia Chinetti Bart Staels

Peroxisome proliferator-activated receptor γ polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes

Aim One putative determinant of diabetic nephropathy is the Pro12Ala (P12A) polymorphism in the gene encoding peroxisome proliferator-activated receptor γ (PPARγ). Previous research has found a “protective” role for the A12 allele in association with type 2 diabetes, atherosclerosis, and measures of kidney damage. The objective of this study was to investigate a possible role for the P12A PPARγ gene polymorphism with diabetic nephropathy in an isolated aboriginal Canadian population at high risk for renal disease. Methods The P12A PPARγ gene polymorphism was genotyped in 159 subjects (62 men and 97 women) of Oji–Cree descent. Participants were selected from a communitywide survey, which included diabetic nephropathy assessment by albumin/creatinine (A/C) ratio measurement. Genetic associations were tested by multivariate regression analysis, using a forward stepwise modeling approach. Results PPARγ A12 allele carriers had reduced prevalence of microalbuminuria with a ∼1.5-fold reduction in A/C ratio. Both PPARG P12A genotype [odds ratio (OR)=0.25, 95% confidence interval (95% CI)=0.076–0.85, P=.026] and systolic blood pressure (OR=1.69, 95% CI=1.15–2.48, P=.0075) were associated with microalbuminuria. Conclusions The genetic influence of PPARG P12A genotype is modest and is overshadowed by duration of diabetes and systolic blood pressure as the major risk factors for diabetic nephropathy in the Oji–Cree population. The observed genetic association with diabetic nephropathy, however, confirms earlier findings, highlighting the importance of this polymorphism.

Energy balance and food intake: The role of PPARγ gene polymorphisms

Mechanisms regulating energy balance involve complex interactions between genetic, environmental and behavioural (learnt and intrinsic) factors. Genotype may drive the partitioning of energy metabolism and predispose to site-specific adiposity, culminating in a state of energy imbalance. One candidate gene with a direct link to adiposity is the peroxisome proliferator-activated receptor γ ( PPARG) gene. PPARG is a cell nuclear receptor expressed almost exclusively in adipose tissue that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity. PPARγ appears to be a key regulator of energy balance, with polymorphisms on the PPARG gene linked to obesity and effects on body composition. Our research has confirmed an association between the pro12ala allele and reduced incidence of obesity in pre-pubertal children and there are strong associations between genetic variation at the PPARG locus and percentage body fat. Moreover, our evidence suggests that PPARG C-681G and pro12ala polymorphisms display opposing effects in terms of growth phenotype, with pro12Ala associated with deficient energy utilisation, leading to reduced growth and the G-681 variant associated with accelerated growth compared with wildtypes. Common differences in this gene have also been associated with variations in body weight in response to dietary macronutrients. Preliminary evidence suggests that PPARG variants may even be involved in the control of short term energy compensation. Taken together these data suggest that the role of PPARG is varied and complex, influencing fat deposition and growth velocity early in life, with potential impact in the control of energy intake and appetite regulation, and could provide a key target for future research and anti-obesity agents.

PPARs and Bone Metabolism

Welcome to the inaugural special issue of PPAR Research: PPARs and Bone Metabolism. In addition to the key roles PPARs play in numerous processes including glucose and fat metabolism, inflammation, cancer, and central nervous system maintenance, a new role for PPAR-γ has recently emerged: the maintenance of bone homeostasis during aging and disease. In this premier issue we have assembled what is close to a comprehensive overview of the role of PPAR-γ in the control of bone maintenance. This takes into account PPAR-γ's role in mesenchymal stem cell lineage allocation, possible cross-talk with relevant nuclear receptors, examination of PPAR-γ gene polymorphisms and bone mineral density in humans, a role of PPAR-γ in bone loss due to skeletal disuse, evidence that human bone is vulnerable to antidiabetic therapies with PPAR-γ agonists, the thiazolidinediones, and evidence that the antiosteoblastic activity of PPAR-γ can be separated from its proadipocytic and antidiabetic activities by using selective modulators. We also present a novel hypothesis that PPAR-γ acts as a regulator of chondrocyte development and cartilage homeostasis. We realize that we have not covered all aspects of PPARs involvement in the control of bone maintenance; however, this introduction should serve as a competent first attempt to present these new aspects of bone biology to the broader audience of our readers. Beata Lecka-Czernik

Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ gene in first-degree relatives of subjects with polycystic ovary syndrome

Aim. This study was designed to examine the relationship between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene and insulin resistance (IR) in first-degree relatives of subjects with polycystic ovary syndrome (PCOS).Materials and methods. One hundred and twenty family members of 55 patients with PCOS and 80 unrelated healthy control subjects without a family history of diabetes or PCOS were studied. IR was assessed by homeostatic model assessment (HOMA-IR) and area under the curve (AUC) for insulin during an oral glucose tolerance test in subjects with normal glucose tolerance and controls. Genetic analysis of the PPAR-γ gene Pro12Ala polymorphism was performed by restriction fragment length polymorphism.Results. Fasting insulin, HOMA-IR and AUC insulin were significantly higher in first-degree relatives of PCOS subjects than in controls. A significantly different allele distribution of the Pro12Ala polymorphism of PPAR-γ was observed between the two groups, with the frequency of the variant Ala isoform being significantly reduced in the first-degree relatives of PCOS subjects (10.8%, 13 subjects) compared with the control group (22.5%, 18 subjects). All Pro12Ala polymorphisms of the PPAR-γ gene were heterozygous. Compared with first-degree relatives of PCOS subjects with the Pro12Pro polymorphism of PPAR-γ, first-degree relatives of PCOS subjects with the Pro12Ala polymorphism had low fasting insulin, HOMA-IR and AUC insulin levels. The combined prevalence rate for impaired glucose tolerance, impaired fasting glucose and diabetes was 40% (16 subjects) in mothers and 52% (20 subjects) in fathers of PCOS women.Conclusion. Our findings suggest that Pro12Ala PPAR-γ gene polymorphism may be protective against IR and might prevent the development of diabetes mellitus in the first-degree relatives of subjects with PCOS.

Gene–gene interaction of PPARγ and ApoE affects coronary heart disease risk

Background: Apolipoprotein ε4 has been proposed as a genetic predictor for CHD. Peroxisome proliferator-activated receptors (PPAR), a recent identified nuclear transcription factor, is involved in regulation of many target genes and plays an important role in lipid metabolism, insulin sensitivity, obesity and atherosclerosis. PPARγ gene polymorphisms may affect the profile of CHD-related risk factors. Hypothesis: Interaction between PPARγ gene polymorphism and apoE polymorphisms affect the presence of CHD. Method: This is a case–control study, which enrolled 150 cases with CHD and 157 controls without CHD. Polymerase chain reaction-restricted fragments length polymorphism was used to determine the apoE genotype and PPARγ C161→T substitution. Results: ApoE ε4 allele was significantly more prevalent in CHD patients than in controls (13.05 vs. 7.35%, P<0.05). The apoE ε4 carries had significant higher LDL-C levels than other apoE carriers and this tendency could be modified by PPARγ CT genotype. ApoE genotype ε4 was an independent risk factor for CHD (OR=4.29, 95%CI: 1.6–11.48, P=0.004). A significant interaction between apoE ε4 and PPARγ CT genotype was detected with respect to the effect on CHD ( P=0.045). Conclusion: This is the first study to explore the effect of interaction between PPARγ C161→T variant and apoE ε4 genotype. The result exhibited an interaction effect of two genes on serum cholesterol level. The association of CHD to apoE genotype was subjected to the attenuation effect of PPARγ CT genotype.

PPARγ gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men

Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-γ (PPARγ) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARγ gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARγ gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment–insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (ΔIRI, Pro/Pro 0.55 ± 3.49 μU/mL v Pro/Ala −2.83 ± 1.47 μU/mL, P <.05; ΔHOMA-R, Pro/Pro 0.09 ± 0.86 v Pro/Ala −0.61 ± 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARγ gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome. Copyright 2003, Elsevier Science (USA). All rights reserved.

2P-0404 The dopaminergic D2 and PPARγ2 gene polymorphism in patients with familial obesity

2P-0404 The dopaminergic D2 and PPARγ2 gene polymorphism in patients with familial obesity

Impact of Two Common Polymorphisms in the PPARγ Gene on Glucose Tolerance and Plasma Insulin Profiles in Monozygotic and Dizygotic Twins

The Pro12Ala polymorphism in the PPARgamma2 gene has been associated with reduced risk of type 2 diabetes and insulin resistance. Recently, an association between dizygotic twinning and PPARgamma gene polymorphisms has been proposed. We investigated the phenotypic appearance of the two polymorphisms (Pro12Ala and exon 6 C-->T) in PPARgamma among elderly twins (207 monozygotic [MZ] and 342 dizygotic [DZ]) and evaluated whether they could explain previously reported differences in plasma glucose and insulin profiles among MZ and DZ twins. We demonstrated a significant impact of the Pro12Ala polymorphism on glucose tolerance, diabetic status, homeostasis model assessment for insulin resistance, and plasma insulin profiles in twins. No impact of the silent exon 6 polymorphism on glucose homeostasis or plasma insulin profiles was found. Independent of the polymorphisms, we observed a significant impact of zygosity status per se on the plasma insulin profile after oral glucose ingestion, with the MZ twins being more hyperinsulinemic, indicating insulin resistance, than the DZ twins. Nonsignificantly higher glucose concentrations were observed among MZ compared with DZ twins. We demonstrated an association between the Ala allele and reduced risk of diabetes and insulin resistance in twins. However, the differences in metabolic profiles among MZ and DZ twins were not explained by differences in frequencies of the genetic variants and may be due to intrauterine environmental factors operating in twins independent of genotype. Accordingly, our study simultaneously supports a role for both the intrauterine environment (thrifty phenotype) and for genetics (thrifty genotype) in the etiology of insulin resistance and perhaps glucose intolerance in twins.