P12A Polymorphism Research Articles

Peroxisome proliferator-activated receptor γ Pro12 ala polymorphism and risk of cerebral stroke in type 2 diabetes mellitus egyptian patients.

This study aimed to analyze the association of the peroxisome proliferator activated receptor gamma (PPARγ) P12A (rs1801282) polymorphism with development of cerebral stroke in patients with type 2 diabetes mellitus. We included 224 patients with diabetes, they were categorized into116 patients with ischemic stroke (IS) and 108 without IS, in addition to 148 healthy controls in this study. respectively. Anthropometric parameters and laboratory tests were measured. The polymorphism was detected by a PCR-RFLP method. A12 allele and A12 containing genotypes show significant higher percentage in patients with diabetes and IS in comparison to diabetes patients without IS (9.1 vs. 4.2%,16.4 vs7.4%; P = 0.044,0.044) with OR of 2.29 and 2. 449 respectively (95% CI: 1.024-5.115, 1.024-5.856) but does not withstand Bonferroni correction. A12 containing genotypes and A12 allele are not associated with IR, diabetes and risk of IS development, however, significant higher BMI were observed in A12 allele carriers in the studied patients with diabetes as well as those with IS.

The PPARγ2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus.

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA+AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95% CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95% CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n=3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95% CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus.

Variants of PGIS and PPARγ in Idiopathic Pulmonary Arterial Hypertension

Introduction: Idiopathic Pulmonary Arterial Hypertension (IPAH) is a subset of a heterogeneous group of diseases called Pulmonary Arterial Hypertension (PAH), characterized by elevated pulmonary arterial pressure (PAP) and is associated with severe arteriopathy, vascular lesions, and right heart failure. The role of prostacyclin synthase, an enzyme responsible for production of prostacyclin, and peroxisome proliferator-activated receptor gamma, involved in many cellular activities, is studied here. Objectives: The objective of the study is to determine any association of prostacyclin synthase and Peroxisome proliferator-activated receptor gamma with Idiopathic Pulmonary Arterial Hypertension Materials and methods: A total of 77 IPAH patients and 100 controls were genotyped using PCR SSCP and RFLP, and appropriate statistical tests were employed to determine the significance and to interpret the results. Results and conclusion: This study has attempted to correlate promoter/gene polymorphisms of PGIS to its activity, and it can be concluded that the VNTR polymorphism and the polymorphism found in exon 6 may not have an effect on the levels of PGIS. The alanine variant of P12A polymorphism of PPARγ was found to be significantly associated with a reduced risk of IPAH.

The PPAR γ (P12A) Locus-Associated Diabetes Risk is Modulated by Central Obesity in Punjabi Sikhs

Background: Several studies have reported a common proline-to-alanine substitution (P12A) in the peroxisome proliferator-activated receptor gamma (PPARγ) gene to be invariably associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and dyslipidemia. The purpose of this study was to determine whether the PPARγ gene (P12A) polymorphism contributes to susceptibility to T2DM and central obesity in Khatri Sikh community from India. Methods: We studied 1711 subjects comprising 1186 individuals from 324 families and 525 unrelated nondiabetic controls. We tested the association between T2D and P12A polymorphism using logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on obesity, glucose homeostasis and lipid traits using multiple linear regression analysis. Results: Our findings could not confirm the association of PPARγ polymorphism with T2DM in this familybased sample. However, the comparison of unrelated controls with affected relatives (n=537) revealed a marginally significant association with this locus with T2DM (odds ratio (OR) 1.48, P=0.016). However, in the data stratified by traits related to abdominal obesity, there was a significant increase in T2DM risk in the individuals with waist circumference (>37 inches, OR 3.51, P=0.005) and waist to hip ratio (>0.95, OR 3.02, P= 0.003) in younger relatives. Conclusions: PPARγ (P12A) locus appears to have profound influence in promoting insulin sensitivity through its interaction with central obesity particularly at younger age.

Role of the ACE ID and PPARG P12A Polymorphisms in Genetic Susceptibility of Diabetic Nephropathy in a South Indian Population

BackgroundDiabetic nephropathy (DN) is one of the life-threatening disorders characterized by persistent albuminuria, raised arterial blood pressure, a lowered glomerular filtration rate, and high risk of cardiovascular morbidity and mortality. The vascular genes ACE (Angiotensin-converting enzyme), and PPARG (peroxisome proliferator activated receptor gamma) are involved in alterations in vascular endothelium, and are suggested to play a role in the susceptibility of diabetic nephropathy.ObjectivesThe aim of our study was to find out the role of ACE ID and PPARG P12A polymorphisms in genetic susceptibility of diabetic nephropathy in south Indian population.Patients and MethodsA total of 54 cases with diabetic nephropathy and 67 control subjects with diabetes were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and genotyped using PCR-electrophoresis (ACE ID) or PCR-RFLP (PPARG P12A) methods.ResultsACE ID genotypes followed Hardy-Weinberg equilibrium in both cases and controls. But P12A genotypes deviated from Hardy-Weinberg equilibrium in diabetic controls. Chi2 test was applied for the analysis of genotypic distributions in genotypic and dominant models. Odds ratios were also calculated. No significant differences in genotype frequencies of ACE ID and PPARG P12A polymorphisms were found on comparing patients with diabetic nephropathy with diabetic controls. The synergistic role of ACE ID* PPARG P12A interaction, did not show any association in patients with diabetic nephropathy when compared to diabetic controls.ConclusionsIn conclusion, the ACE and PPARG genes do not have a key role in conferring risk for diabetic nephropathy.

Quantitative assessment of the influence of PPARG P12A polymorphism on gestational diabetes mellitus risk

The peroxisome proliferator-activated receptor-γ (PPARG) is a member of the nuclear hormone receptor superfamily that has attracted considerable attention as a candidate gene for gestational diabetes mellitus (GDM) based on its function as a key factor involved in the regulation of adipocyte differentiation as well as lipid and glucose metabolism and insulin sensitivity. Many studies have examined the association between P12A polymorphism (rs1801282) in the PPARG gene and risk of GDM, but the results have been inconsistent. To derive a more precise estimation of the relationship, a meta-analysis of 2,858 GDM patients and 6,890 controls from nine published case-control studies was performed. An overall random effects odds ratio of 0.89 (95% confidence interval [CI]: 0.77-1.04, P=0.15) was found for 12A allele. In the subgroup analysis by ethnicity, significantly decreased risks were found in East Asians, while no significant associations were detected among Caucasian and Middle Eastern populations. Similar results were also observed using dominant genetic model. This meta-analysis suggested an overall weak association between the P12A polymorphism and GDM risk among East Asians. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of the PPARG gene on risk of GDM.

The meta-analysis of the association of PPARG P12A, C161T polymorphism and coronary heart disease

Two common variations of peroxisome proliferator-activated receptor γ (PPARG), P12A (Pro12Ala, rs1801282), and C161T (His447His, rs3856806), are thought to have an effect on susceptibility to coronary heart disease (CHD), but the results are inconsistent. Therefore, a meta-analysis of published studies was performed. The electronic databases, PubMed, Embase, Web of Science, and CNKI (China National Knowledge Infrastructure) were searched for studies to include in the present meta-analysis (last search was updated on 30 Aug. 2011). Twenty studies testing the association between PPARG gene polymorphisms and CHD were examined: 12 studies of P12A; 8 studies of C161T. Overall and ethnicity-specific summary odds ratios and corresponding 95% confidence intervals for CHD associated with these polymorphisms were estimated using fixed- and random-effects models. Heterogeneity and publication bias were evaluated. A total of 20 studies including 5,795 cases and 9,069 controls were included in this meta-analysis. No significant associations were found in carriers of the rare Ala allele of the P12A polymorphism versus the common Pro/Pro genotype among the studies with both of the fixed-effect and random-effect model. In the subgroup analyses by ethnicity, source of control and type of study, no significant risks were found. For PPARG C161T, carriers of the T variant of C161T polymorphism were associated with an increased risk of CHD (OR = 1.182, 95% CI: 1.023-1.341, P(heterogeneity) = 0.002), and in the stratified analysis by ethnicity and source of controls, the contrast of CT + TT vs. CC all produced significant association in Asian and hospital-based controls (OR = 1.276, 95% CI: 1.084-1.468, P(heterogeneity) = 0.055; OR = 1.164, 95% CI: 1.001-1.326, P(heterogeneity) = 0.002),when the fixed-effect model was used. But they were all insignificant with the random-effect model. This meta-analysis suggests that the PPARG C161T polymorphism marginally contributes to increased susceptibility to CHD and marginally increased association between PPARG H477H polymorphism and CHD also appeared in Asian and hospital-based controls. But PPARG P12A polymorphism is not associated with CHD risk.

Peroxisome Proliferator Activating Receptor Alpha and Gamma Polymorphisms and Metabolic Abnormalities in HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy: The ANRS CO8 APROCO-COPILOTE Study

Highly active antiretroviral therapy (HAART) is associated with fat redistribution and metabolic disorders. The present study was undertaken to evaluate the association between peroxisome proliferator activated receptor (PPAR)α and PPARγ polymorphisms, two genes involved in lipid metabolism and adipocyte differentiation, and elements of the metabolic syndrome, lipodystrophy, or carbohydrate metabolism abnormalities in patients receiving HAART. The frequency distribution of rare alleles for PPARα (L162V) and PPARγ (P12A and H449H) was compared using the chi square test in 363 HIV-1-infected patients classified according to the presence or absence of the metabolic syndrome after 48 months of follow-up on their first PI-containing regimen. The P12A rare g allele was present in 12% patients with normal glucose metabolism, 11% patients with impaired glucose tolerance or impaired fasting glucose, and 35% patients with diabetes (p=0.014). The rare g allele for L162V was present in 14% of patients free of hypertriglyceridemia and in 7% patients with hypertriglyceridemia (p=0.04). The rare g allele for L162V was found in 15% of patients free of any sign of lipodystrophy and 8% with at least one sign of lipodystrophy (p=0.04) and the rare t allele for H449H was found in 14% of patients free of any sign of lipodystrophy and 23% of patients with at least one sign of lipodystrophy (p=0.05). There was no convincing association between any polymorphism of PPARα and PPARγ and each individual component of the metabolic syndrome, except for the relationship of the P12A polymorphism with diabetes. Confirmatory studies on a larger number of individuals are needed.

Effects of the PPARG P12A and C161T gene variants on serum lipids in coronary heart disease patients with and without Type 2 diabetes

We investigated whether PPAR-γ2 gene polymorphisms are associated with serum lipids and the occurrence of coronary heart disease (CHD) prospectively characterised for the presence or absence of Type 2 diabetes in a Turkish population. Our study included 202 patients with CHD (102 with diabetes, 100 without diabetes) and 105 controls. PPARγ genotypes were determined by PCR-RFLP technique. The PPARγ-C161T CC homozygote genotype was associated with significantly increased CHD risk when compared with the T allele carriers (CT+TT) in CHD patients with diabetes (OR:1.951, 95%CI: 1.115-3.415, P = 0.019), whereas PPARγ-P12A polymorphism was not associated with CHD risk (P > 0.05). Serum HDL-C levels were significantly lower in controls with the P12A heterozygote when compared with the P12P homozygote (P = 0.002). In the CHD patients with diabetes, CT heterozygote genotype showed higher serum triglyceride than the CC homozygote genotype (CT:2.42 ± 1.89 vs. CC:1.61 ± 0.21, P = 0.015). Our findings shows the association of these two polymorphisms with serum triglyceride levels, which was increased in the order of P12P-CC < P12P-CT < P12A-CC < P12A-CT in the CHD patients with diabetes. Furthermore, we observed that the increasing effects of the CT genotype on serum triglyceride levels could be modified by PPARγ P12A polymorphism (P12A-CT:2.30 ± 1.75 vs. P12P-CC:1.79 ± 1.14, P = 0.028). We suggested that homozygote CC genotype of the PPARγ C161T polymorphism might be associated with an increased CHD risk especially in patients with diabetes. We observed that the C161T CT heterozygote genotype shows an unfavorable effect on serum lipid profile in CHD patients with diabetes and this effect was weaken with the presence of P12P homozygote genotype.

PPAR 2 P12A polymorphism and albuminuria in patients with type 2 diabetes: a meta-analysis of case-control studies

Insulin resistance has a role in diabetic nephropathy. The A12 variant of the PPARγ2 P121A polymorphism has been firmly associated with reduced risk of insulin resistance, while its role on the risk of albuminuria in patients with type 2 diabetes is uncertain. This study investigated whether the PPARγ2 P12A polymorphism modulates the risk of albuminuria in these patients. We tested the association between the A12 variant and albuminuria in three new case-control studies in diabetic patients from Italy (n = 841, n = 623 and n = 714 patients, respectively) and then performed a meta-analysis of all studies available to date. The nine studies we meta-analysed (six previously published and three presented here) comprised a total of 2376 cases and 4188 controls. In none of the three new studies was a significant association observed with odds ratio (OR) [95% confidence intervals (95% CI)] being 1.115, 0.799 and 0.849 (P = 0.603, 0.358 and 0.518, respectively). At meta-analysis, the overall OR (95% CI) for association between A12 and albuminuria was 0.694 (0.528-0.912). A significant heterogeneity of the genetic effect was observed (P = 0.026), which was totally explained by the different method of urine collection and albuminuria definition utilized across the studies. In fact, most of the effect was observed in the four studies determining albumin excretion rate rather than in those using albumin concentration in a single spot (OR, 95% CI: 0.529, 0.397-0.706, P = 0.0000164 and 0.919, 0.733-1.153, P = 0.47, respectively). The present study shows that the PPARγ2 Ala12 variant is significantly associated with a reduced risk of albuminuria among patients with type 2 diabetes.

Effects of Peroxisome Proliferator-Activated Receptors, Dietary Fat Intakes and Gene–Diet Interactions on Peak Particle Diameters of Low-Density Lipoproteins

The risk of cardiovascular diseases (CVDs) is modulated by gene–diet interactions. The objective of this study was to examine whether gene–diet interactions affect peak particle diameters (PPD) of low-density lipoprotein (LDL). Methods: The study included 674 participants. A food frequency questionnaire was administered to obtain dietary information. LDL-PPD was determined by non-denaturing 2–16% polyacrylamide gradient gel electrophoresis. Peroxisome proliferator-activated receptor (PPAR) gene polymorphisms PPARα L162V (rs1800206), PPARγ P12A (rs1801282) and PPARδ –87T→C (rs2016520) were determined by PCR-RFLP. Results: Among carriers of thePPARα L162V polymorphism, gene–diet interaction effects on LDL-PPD were observed with saturated fat (p = 0.0005) and total dietary fat (p = 0.006). Among PPARα V162 carriers, subjects with higher saturated fat intakes had smaller LDL-PPD than those with lower intakes (254.23 ± 2.74 vs. 256.21 ± 2.61 Å, respectively, p = 0.007). Among subjects homozygous for the PPARα L162 allele, those with higher saturated fat intakes had larger LDL-PPD than those with lower saturated fat intakes (255.86 ± 2.66 vs. 255.05 ± 2.65 Å, respectively, p = 0.01). Gene–diet interactions were also found for PPARγ P12A polymorphism with saturated fat intake (p = 0.04) and for PPARδ –87T→C with the polyunsaturated/saturated fat ratio (p = 0.0013). Conclusions: These results stress that dietary factors should be included in studies determining the effect of different polymorphisms on CVD risk factors.

PPARγ polymorphisms and cancer risk: A meta-analysis involving 32,138 subjects

The peroxisome proliferator-activated receptor gamma (PPARgamma) has been suggested to act as a tumor suppressor gene. Two common variations of PPARgamma, P12A (Pro12Ala, rs1801282) and C161T (His447His, rs3856806), are thought to have an effect on susceptibility to various carcinomas but the results are inconsistent. In this meta-analysis, we assessed published studies of the association between two common PPARgamma polymorphisms and cancer risk from 26 studies with 27,677 subjects for PPARgamma P12A, from 4 studies with 4,461 subjects for C161T. No significant associations were found in carriers of the rare Ala allele of the P12A polymorphism versus the common Pro/Pro genotype among the studies. In the subgroup analyses by cancer types, carriers of the Ala variant of P12A polymorphism were associated with protection from colorectal cancer (OR=0.84, 95% CI=0.72-0.98, Pheterogeneity = 0.014), but the inverse association was found in gastric cancer (OR=2.31, 95% CI=1.59-3.36, Pheterogeneity = 0.941). In the stratified analysis by ethnicity, no significant risks were found among Asians, Americans and Caucasians. For PPARgamma C161T, no significant associations were found in any of the studies (OR=1.08, 95% CI=0.95-1.23, Pheterogeneity = 0.430) or subgroups. This meta-analysis suggests that the Ala allele of the PPARgamma P12A polymorphism might be a protective factor for colorectal cancer, but a risk factor for gastric cancer. The PPARgamma C161T is marginally associated with cancer susceptibility.

Isomer-specific effects of CLA on gene expression in human adipose tissue depending on PPARγ2 P12A polymorphism: a double blind, randomized, controlled cross-over study

BackgroundPeroxisome proliferator-activated receptor (PPAR)γ is a key regulator in adipose tissue. The rare variant Pro12Ala of PPARγ2 is associated with a decreased risk of insulin resistance. Being dietary PPARγ ligands, conjugated linoleic acids (CLAs) received considerable attention because of their effects on body composition, cancer, atherosclerosis, diabetes, obesity and inflammation, although some effects were only demonstrated in animal trials and the results in human studies were not always consistent. In the present study effects of CLA supplementation on genome wide gene expression in adipose tissue biopsies from 11 Ala12Ala and 23 Pro12Pro men were investigated. Subjects underwent four intervention periods (4 wk) in a randomized double blind cross-over design receiving 4.25 g/d of either cis-9, trans-11 CLA, trans-10,cis-12 CLA, 1:1 mixture of both isomers or a reference linoleic acid oil preparation. After each intervention biopsies were taken, whole genome expression microarrays were applied, and genes of interest were verified by realtime PCR.ResultsThe following genes of lipid metabolism were regulated by CLA: LDLR, FASN, SCD, FADS1 and UCP2 were induced, while ABCA1, CD36 and CA3 were repressed. Transcription factors PPARγ, NFAT5, CREB5 and EBF1, the adipokine NAMPT, members of the insulin signaling cascade SORBS1 and IGF1 and IL6ST were repressed, while the adipokine THBS1 and GLUT4 involved in insulin signaling were induced. Compared to trans-10,cis-12 CLA and the CLA mixture the cis-9, trans-11 CLA isomer exerted weaker effects. Only CD36 (-1.2 fold) and THBS1 (1.5 fold) were regulated. The CLA effect on expression of PPARγ and leptin genes depends on the PPARγ2 genotype.ConclusionThe data suggest that the isomer specific influence of CLA on glucose and lipid metabolism is genotype dependent and at least in part mediated by PPARγ.Trial registration: ISRCTN91188075

PPAR-α L162V and PGC-1 G482S gene polymorphisms, but not PPAR-γ P12A, are associated with alcohol consumption in a Spanish Mediterranean population

Background Peroxisome Proliferator-Activated Receptors (PPARs) and its co-activators are regulatory elements of the cellular lipid homeostasis and have been associated with feeding behavior modulation. Animal models suggest that these genes may be involved in alcohol consumption regulation. However, no studies in humans exist. Our aim is to estimate the possible association between polymorphisms in the PPAR-α, PPAR-γ and PPAR-γ co-activator 1A ( PGC-1A) genes and alcohol consumption in humans. Methods We have conducted a cross-sectional study between the PPAR-α L162V, PPAR-γ P12A and PGC-1A G482S polymorphisms, and alcohol consumption in a general Mediterranean Spanish population (303 men and 443 women). Results We have found an association between the L162V polymorphism and alcohol consumption in which, carriers of the V allele were more prevalent among alcohol consumers (19.4% vs. 9.8%; OR 2.69; 95% CI: 1.31–5.54, p = 0.007). The G482S polymorphism showed a significantly higher frequency in the group of high alcohol drinkers than in non-high alcohol drinkers (33.4% vs. 20.6%; OR 2.28; 95% CI: 1.07–4.88, p = 0.034). Mean alcohol consumption was higher as the number of G alleles increased (GG 8.6 ± 12.8 g/day, GS 6.6 ± 9.2 g/day, SS 5.6 ± 7.8 g/day, p = 0.003). These results remained statistically significant after covariate adjustment. Conclusions PPAR-α L162V and PGC-1A G482S polymorphisms are associated with alcohol consumption in the Mediterranean population.

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.

Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: A case-cohort study and meta-analyses

The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confirmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS. We performed a case-cohort study in 15,236 initially healthy Dutch women and applied a Cox proportional hazards model to study the relation of the P12A polymorphism and AMI (n = 71), CHD (n = 211), and IS (n = 49) under different inheritance models. In addition, meta-analyses of published studies were performed. Under the dominant inheritance model, carriers of the alanine allele compared with those with the more common genotype were not at increased or decreased risk of CHD (hazard ratio [HR] = 0.82; 95% confidence interval [CI], 0.58 to 1.17) and of IS (HR = 1.03; 95% CI, 0.14 to 7.74). In addition no relations were found under the recessive and additive models. Our meta-analyses corroborated these findings by showing no significant association. For AMI we found a borderline significant association under dominant (HR = 0.49; 95% CI, 0.26 to 0.94), and additive (HR = 0.51; 95% CI, 0.26 to 1.00) models which could be due to chance, because of small cases in this subgroup. The meta-analysis did not show any association between the polymorphism and risk of AMI under the different genetic models. Our study in healthy Dutch women in combination with the meta-analyses of previous reports does not provide support for a role of P12A polymorphism in PPARG gene in MI and CHD risk. Also our study shows that the polymorphism has no association with IS risk.

Interaction of DIO2 T92A and PPARγ2 P12A Polymorphisms in the Modulation of Metabolic Syndrome

Type 2 iodothyronine deiodinase (DIO2) converts thyroid prohormone tetraiodothyronine into the biologically active triiodothyronine hormone, which increases insulin sensitivity at the skeletal muscle level. The DIO2 T92A polymorphism modulates deiodinase activity and has been inconsistently associated with insulin resistance. Also, the P121A polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene, which encodes a transcription factor involved in insulin signaling, has been inconsistently associated with insulin resistance. This study was aimed at evaluating the combined effect of DIO2 T92A and PPARgamma2 P12A polymorphisms on insulin resistance-related features in 590 non-diabetic whites. A significant gene-gene interaction was observed in the modulation of systolic (p = 0.01) and diastolic (p = 0.02) blood pressure and metabolic syndrome (p = 0.02), with carriers of both DIO2 A92 and PPARgamma2 A12 variants showing the worst phenotype. This latter interaction was also shown by multifactor dimensionality reduction analysis (p = 0.0045). A peroxisome proliferator response element in the DIO2 promoter was identified by in silico analysis and confirmed by in vitro gel shift mobility assay, thus providing a biological plausibility for the observed gene-gene interaction. If confirmed in other populations, comprising several thousand individuals, these data may help identify individuals at risk for insulin resistance-related abnormalities.

Effects of the Type 2 Diabetes-AssociatedPPARGP12A Polymorphism on Progression to Diabetes and Response to Troglitazone

The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes. We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo). This study included 3548 Diabetes Prevention Program participants. We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr. Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99-1.57; P=0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P=0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr. The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.

Pilot Study of Rosiglitazone Therapy in Women with Breast Cancer: Effects of Short-term Therapy on Tumor Tissue and Serum Markers

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a steroid nuclear receptor that is activated by natural compounds such as specific fatty acids and synthetic drugs such as thiazolidinedione antidiabetic agents. Expressed in normal and malignant mammary epithelial cells, activation of PPARgamma is associated with antiproliferative effects on human breast cancer cells in preclinical studies. The purpose of this study was to test the hypothesis that PPARgamma ligand therapy might inhibit tumor growth and progression in human breast cancer. We conducted a pilot trial of short-term (2-6 weeks) treatment with the thiazolidinedione rosiglitazone in 38 women with early-stage (T(is)-T(2), N(0-1), M(0)) breast cancer, administered between the time of diagnostic biopsy and definitive surgery. Short-term treatment with rosiglitazone (8 mg/d) did not elicit significant effects on breast tumor cell proliferation using Ki67 expression as a measure of cell proliferation and surrogate marker of tumor growth and progression. In pretreatment tumors notable for nuclear expression of PPARgamma by immunohistochemistry, down-regulation of nuclear PPARgamma expression occurred following rosiglitazone administration (P = 0.005). No PPARG mutations were identified, and the incidence of P12A and H446H polymorphisms did not differ relative to U.S. controls (P = 0.5). Treatment with rosiglitazone resulted in increased serum adiponectin (P < 0.001), decreased insulin levels (P = 0.005), and increased insulin sensitivity (P = 0.004). Rosiglitazone was well tolerated without serious adverse events. Our data indicate that short-term rosiglitazone therapy in early-stage breast cancer patients leads to local and systemic effects on PPARgamma signaling that may be relevant to breast cancer.

The Peroxisome Proliferator-Activated Receptor- 2 P12A Polymorphism and Type 2 Diabetes in an Arab Population

The association of type 2 diabetes with the P12A polymorphism of the peroxisome proliferator–activated receptor gene ( PPAR-γ2 ) has been established in several populations (1). However, no studies have thus far been reported for Arab populations. While many variants have been identified in this gene, the most prevalent and best studied is the P12A polymorphism. There is considerable interpopulation variance in the incidence of the risk allele (P12). This ranges in frequency from a high of 0.96–0.98 in populations including the Japanese, Chinese, and African Americans to 0.91 in …