A personalised diet approach study: Interaction between PPAR-γ Pro12Ala and dietary insulin indices on metabolic markers in diabetic patients.

BACKGROUND: The present study aimed to investigate the effect of the interaction between peroxisome proliferator-activated receptor gamma (PPAR-γ) Pro12Ala polymorphisms and dietary insulin load and insulin index (DIL and DII) on cardio-metabolic markers among diabetic patients. METHODS: This cross-sectional study was conducted on 393 diabetic patients. A food-frequency questionnaire was used for DIL and DII calculation. PPAR-γ Pro12Ala was genotyped by a polymerase chain reaction-restriction fragment length polymorphism method. Biochemical markers, including total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride, superoxide dismutase, C-reactive protein, total antioxidant capacity, pentraxin-3, isoprostaneF2α, interleukin-18, leptin and ghrelin, were measured by a standard protocol. RESULTS: Risk-allele carriers (CG, GG) had higher obesity indices [body mass index (pinteraction = 0.006) and WC (pinteraction = 0.04)] compared to individuals with the CC genotype when they consumed a diet with higher DIL and DII respectively. Besides, carriers of the G-allele who were in the highest tertile of DIL had lower high-density lipoprotein (pinteraction = 0.04) and higher isoprostaneF2α (pinteraction = 0.03) and pentraxin-3 (pinteraction = 0.03). Moreover, the highest tertile of the DII, showed an increase in interleukin-18 (pinteraction = 0.01) and lower superoxide dismutase (pinteraction = 0.03) for risk-allele carriers compared to those with CC homozygotes. CONCLUSIONS: We revealed that the PPAR-γ Pro12Ala polymorphism was able to intensify the effect of DIL and DII on cardiovascular disease risk factors; risk-allele carriers who consumed a diet with high DIL and DII score were more likely to be obese and have higher inflammatory markers. Also, protective factors against cardiovascular disease risk factors were reduced significantly in this group compared to CC homozygotes.

Peroxisome Proliferator-Activated Receptor Gamma Pro12Ala/C161T Genotypes and Risky Haplotype Altering Risk of Breast Cancer: A Turkish Case-Control Study.

Breast cancer (BC) has a high incidence rate among women worldwide, and the mechanisms and etiology of this disease are not yet fully understood. The peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor that plays important roles in energy metabolism and cellular differentiation, is also suggested to be effective in cancer development. However, the results of studies investigating the cancer association with PPARgamma are inconsistent, creating a need for further investigation of the effects of this transcription factor on BC risk. We have examined the Pro12Ala-(rs1801282) and C161T-(rs3856806) polymorphisms of the PPARgamma gene in Turkish patients with BC in this case-control study. A total of 95 women diagnosed with BC as cases and 119 controls were genotyped for PPARgamma polymorphisms by polymerase chain reaction and restriction fragment length polymorphism techniques. The ProPro genotype and T161 allele were associated with an increased risk of BC comparing with the Ala12 allele and CC161 genotype, respectively (p < 0.001). The multivariate regression analysis confirmed that the ProPro genotype (p < 0.011), T161 allele (p < 0.001), smoking (p = 0.019), and advanced age (> 60 years) (p = 0.007) are risk factors for breast cancer. We also found that the PPARgamma Pro12Ala and C161T polymorphisms were in linkage disequilibrium (D':0.511, r2:0.099). It was determined that carrying ProPro-T161 risky PPARgamma haplotype was associated with a higher risk of BC compared to protective Ala12-CC161 haplotype (p < 0.01, OR:7.797, 95% CI:3.521-17.263). We concluded that PPARgamma Pro12Ala and C161T polymorphisms are associated with increased BC risk, and ProPro-T161 risky haplotype, which is in linkage disequilibrium, increases this effect.

Association study of rs1801282 PPARG gene polymorphism and immune cells and cytokine levels in a Spanish pregnant women cohort and their offspring.

BACKGROUND: Peroxisome proliferator activated receptor gamma (PPARG) belongs to the nuclear receptor superfamily functioning as transcription factors to regulate cellular differentiation, development and metabolism. Moreover, it has been implicated in the regulation of lipid metabolism, as well as the maturation of monocytes/macrophages and the control of inflammatory reactions. The aim of this study was to evaluate the relationship between the Pro12Ala (rs1808212) PPARG gene polymorphism on immune molecular and cellular components in mothers and their offspring participating in the PREOBE study. METHODS: DNA from maternal venous blood samples at 24, 34 and 40 gestational weeks, plus cord blood samples was extracted. Pro12Ala PPARG polymorphism genotyping was performed, and immune system markers were analyzed by flow cytometry. RESULTS: Study findings revealed no effect of rs1808212 PPARG genotypes on innate immune parameters in mothers and their offspring; however, CD4 + /CD8 + ratio were decreased at 24 and 34 weeks in pregnant women carrying the CG (Pro12Ala) rs1808212 polymorphism, (p = 0,012 and p = 0,030; respectively). Only CD19 levels in peripheral blood were significantly higher at delivery in pregnant women carrying the CC (Pro12Pro) genotype (p ≤ 0.001). Moreover, there were statistically significant differences in leukocytes and neutrophils maternal levels at 34 weeks of gestation, being lower in carriers of Pro12Ala genotype (p = 0.028 and p = 0.031, respectively). CONCLUSIONS: Results suggest that Pro12Ala PPARG polymorphism may have an effect on some cell and immune parameters in pregnant women during pregnancy and at time of delivery. However, newborn innate immune system does not seems to be influenced by PPARG Pro12Ala polymorphism in cord blood.

PPARG Pro12Ala Ala carriers exhibit greater improvements in peripheral insulin sensitivity in response to 12 weeks of aerobic exercise training.

The Ala allele of PPARG Pro12Ala ( rs1801282 ) is associated with greater improvements to the glucose metabolism in exercise studies, but whether this extends to peripheral insulin sensitivity is unknown. Our objective was to investigate the effect of PPARG Pro12Ala on exercise-induced changes in peripheral insulin sensitivity. A total of 124 (91 Pro homozygotes and 33 Ala carriers) previously physically inactive healthy young men and women with overweight or class 1 obesity who completed a 12 wk aerobic exercise intervention were included in the analysis. All participants underwent a hyperinsulinemic euglycemic clamp before and after the 12 wk intervention. The prescribed exercise frequency was 5-7 days/wk, and the exercise energy expenditure was 2,100 4,200 kcal/wk for men and 1,600 kcal/wk for women. Insulin sensitivity improved significantly in both genotype groups. However, Ala carriers had a 1.13-fold (95% confidence interval 1.01; 1.26, P = 0.032) greater improvement in insulin sensitivity from baseline compared with Pro homozygotes. Our data support that PPARG Pro12Ala modifies the effect of aerobic exercise on peripheral insulin sensitivity.

The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated with an increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus.

BACKGROUND: The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Several studies have demonstrated a significant association between Pro12Ala polymorphism of the PPAR-γ2 gene and metabolic disorders. Therefore, this study aimed to evaluate the association of Pro12Ala polymorphism with increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus. METHODS: This cross-sectional study was performed on 145 healthy control subjects and 145 NAFLD patients with a history of type 2 diabetes. Pro12Ala polymorphism genotyping was performed using PCR-restriction fragment length polymorphism (RFLP) technique with the Bs1I restriction enzyme. RESULTS: Our results demonstrated that CC and GG genotypes of Pro12Ala were found in the participants, but there was no statistically significant difference between NAFLD patients and healthy controls (P = 0.64 and χ2 = 0.21). CONCLUSION: This study suggests that Pro12Ala polymorphism of the PPAR-γ2 gene cannot be considered as a risk factor for NAFLD in the Iranian population.

Uric acid and obesity-related phenotypes in postmenopausal women.

The aim of this study was to find the genetic, metabolic, and nutritional risk factors, which can be associated with uric acid (UA) level. The risk factors related to uricemia were assessed among 271 postmenopausal women without cardiometabolic disorders and hypolipidemic/hypoglycemic treatment selected from a cohort of 1423 obese postmenopausal women. The bioimpedance analysis and biochemical and genetic analyses were performed in two groups characterized by serum UA ≥ 4 mg/dL (238 µmol/L) and < 4 mg/dL. The TaqMan-based real-time PCR method was applied to assess the role of Pro12Ala of peroxisome proliferation-activated receptor (PPAR)gamma-2 and Trp64Arg of beta-3-adrenergic receptor (ADRB) polymorphisms. Women with UA level ≥ 4 mg/dL were characterized by larger body mass, triceps skinfold, waist circumference, body fat amount, and serum insulin, glucose, and triglyceride levels. There was no difference in dietary habits between the analyzed groups. Body mass, waist circumference, body fat amount, diastolic blood pressure, and serum insulin, glucose, high-density lipoprotein, and triglyceride levels, Homeostasis Model Assessment-Insulin Resistance, and energy from the dietary fat influence the UA level ≥ 4 mg/dL; however, the serum UA was not determined by Pro12Ala and Trp64Arg polymorphism analyses. The model of linear regression revealed that the group characterized by body mass index  ≥ 25 kg/m2 and glucose ≥ 100 mg/dL has 4 times increased risk of UA level (p = 0.0009); after adding triglycerides ≥ 150 mg/dL, the risk of UA increased 7 times (p = 0.0216). Increasing the level of UA ≥ 4 mg/dL is associated with overweight, hyperglycemia, and hypertriglyceridemia in women without a history of cardiometabolic disorders. A better management of metabolic factors could help prevent further increase in UA levels.

c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2.

Adipocyte differentiation, or adipogenesis, is a complex and highly regulated process. A recent proteomic analysis has predicted that the nonreceptor tyrosine kinase Abelson murine leukemia viral oncogene (c-Abl) is a putative key regulator of adipogenesis, but the underlying mechanism remained obscure. We found that c-Abl was activated during the early phase of mouse 3T3-L1 preadipocyte differentiation. Moreover, c-Abl activity was essential and its inhibition blocked differentiation to mature adipocytes. c-Abl directly controlled the expression and activity of the master adipogenic regulator peroxisome proliferator-activator receptor gamma 2 (PPARγ2). PPARγ2 physically associated with c-Abl and underwent phosphorylation on two tyrosine residues within its regulatory activation function 1 (AF1) domain. We demonstrated that this process positively regulates PPARγ2 stability and adipogenesis. Remarkably, c-Abl binding to PPARγ2 required the Pro12 residue that has a phenotypically well-studied common human genetic proline 12 alanine substitution (Pro12Ala) polymorphism. Our findings establish a critical role for c-Abl in adipocyte differentiation and explain the behavior of the known Pro12Ala polymorphism.

Association of peroxisome proliferator-activated receptor γ Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population.

Association of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala gene polymorphism with type 2 diabetic nephropathy (T2DN) risk in Caucasians is still not clear. This investigation was conducted to assess if there was an association between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians using meta-analysis. The relevant literatures were identified from PubMed, and Cochrane Library on 10 October 2013, and eligible studies were included and synthesized. Six reports including eight studies were recruited into this meta-analysis for the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk in Caucasians. The Pro/Pro genotype was shown to be associated with T2DN risk in Caucasians. However, the Ala/Ala genotype and Ala allele were not associated with T2DN risk in Caucasians. In the sensitivity analysis, according to the control source from hospital, the control source from population, the genotyping methods using PCR-RFLP, Taqman, sample size of case <100, the association of the PPARγ Pro12Ala gene polymorphism with T2DN risk was similar to those in non-sensitivity analysis. In conclusion, the PPARγ Pro/Pro genotype was associated with T2DN risk in Caucasians, but the Ala/Ala genotype and Ala allele not. However, additional studies are required to firmly establish a correlation between the PPARγ Pro12Ala gene polymorphism and T2DN risk in Caucasians.

Genetic polymorphism of Pro12Ala in type 2 diabetes mellitus: Role in inflammation linked to Insulin resistance.

Peroxisome Proliferator-Activated Receptor gamma 2 (PPARγ2) belongs to nuclear receptor superfamily and plays a role in adipocyte differentiation and inflammation. Evidences suggest that inflammatory processes hold key to insulin resistance and PPARγ2 has also been implicated. PPARγ2 exhibits gene polymorphism. The Ala allele of Pro12Ala polymorphism (rs1801282) is associated with a reduced risk for insulin resistance. We attempted the study in overweight and obese males to generate evidences linking insulin resistance, inflammatory mediators, and gene polymorphism of PPARγ2 in overweight and obese males. The conventional biochemical parameters were estimated using established methods. Adiponectin and Haptoglobin were quantitated by ELISA, whereas Ferritin and hs-CRP were by chemi-luminescence. Indices of insulin sensitivity /Insulin resistance were computed based on established formulae. Gene analysis was based on PCR and RFLP. Appropriate statistical analysis was enabled to project gene polymorphism.The heterozygous variant (CG) was around 8 and 38 percent respectively in overweight and obese males. The G Allele was 3.89% and 18.82%. The wild type and heterozygous variant of PPARγ2 depicted significance with haptoglobin, whereas adiponectin showed significance in the wild type. Chi-square test was performed to assess the relation between polymorphic genotypes and ferritin emerged significant. Indices of insulin resistance showed different characteristics with wild type and heterozygous variant ofPPARγ2 gene polymorphism. The inflammatory mediators (hs-CRP, Ferritin, Haptoglobin and adiponectin) exhibited variegated characteristics with the wild type and heterozygous variant of PPARγ2, thus pointing to the nexus among insulin resistance, inflammation, and adipocyte differentiation.

Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-ß/δ Polymorphisms.

Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. OBJECTIVE: To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-ß/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-ß/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. RESULTS: minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-ß/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. CONCLUSIONS: PPAR-γ2 rs1801282 and PPAR-ß/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.

Associations of peroxisome proliferator-activated receptor-γ Pro12Ala polymorphism with non-alcoholic fatty liver disease: A meta-analysis.

BACKGROUND: Polymorphisms in peroxisome proliferator-activated receptor-γ pro12Ala (PPAR-γ Pro12Ala) have been associated with Non-alcoholic Fatty Liver Disease (NAFLD) in several studies. However, the results of these studies are not entirely consistent. Thus, we performed a meta-analysis to investigate the association between the PPAR-γ Pro12Ala polymorphisms and NAFLD. METHODS: Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95 % confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: Relevant medical researches show that 11 studies have been conducted on the analysis of NAFLD for meta-analysis, with a total of 2404 cases and 3959 participating controls. Meta-analysis results show that PPAR-γ Pro12Ala polymorphism and NALAD Ala alleles[no association between dominance model (OR = 0.968, 95%CI: 0.734-1.276, P = 0.815); Pro/Ala vs. Pro/Pro (OR = 0.930, 95 % CI: 0.701-1.233, P = 0.612); Ala/Ala vs. Pro/Pro (OR = 1.220, 95 % CI: 0.668-2.230, P = 0.518); recessive model (OR = 0.907, 95 % CI: 0.516-1.596, P = 0.736)]. Moreover, stratification by ethnicity also revealed that no matter it is in Caucasian populations or in Asian populations, NAFLD has no association with the PPAR-γ Pro12Ala polymorphism. CONCLUSIONS: According to the meta-analysis, both in Asians and Caucasian populations, the PPAR-γ Pro12Ala polymorphism can't be demonstrated to have any link with susceptibility to NAFLD.

The role of the PPARG (Pro12Ala) common genetic variant on type 2 diabetes mellitus risk.

BACKGROUND: Type 2 diabetes (T2DM) prevalence has been rapidly increasing in the last decades. T2DM pathogenesis is related to insulin resistance and beta-cell dysfunction. Peroxisome proliferator-activated receptor gamma (PPARG) is concerned about T2DM risk through the involvement in adipocyte differentiation and energy homeostasis. The present study aimed to find the risk associated with a common genetic variant (Pro12Ala) of the PPARG gene in the development of T2DM in a group of the Iranian population. METHODS: Totally, 149 patients with T2DM and 96 healthy individuals were recruited in this case-control study. The genotyping of the genetic variant was carried out using the polymerase chain reaction (PCR) followed by Sanger sequencing. RESULTS: No significant difference is observed between the CG and GG genotypes frequency of the PPARG variant (P = 0.17) in T2DM patient and the control groups. Furthermore, the frequency of the G allele was similar between case and control groups. The Pro12Ala variant may decrease the risk of diabetic retinopathy (DR) which was not statistically significant. Furthermore, the Pro12Ala variant caused a 27% increase in the risk of diabetes nephropathy (DN) among patients with T2DM but was not significant. CONCLUSIONS: Our findings showed that the PPARG variant could not impact on T2DM development and its complications.

PPARγ2 Pro12Ala Polymorphism is Associated in Children With Traits Related to Susceptibility to Type 2 Diabetes.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. Pharmacological activators of PPARγ are being used as a treatment of obesity related disorders such as dyslipidaemia and type 2 diabetes, but questions remain open regarding the effects of PPARγ on traits related to the development of type 2 diabetes. In our study, we have analyzed the relationship of the common variant Pro12Ala in the human PPARγ2 gene with the presence of obesity and with insulin, HOMA and lipid profile in a representative sample of 6-to 8-year-old children free from the confounding factors associated with adults. We found that Ala12Ala genotype was significantly more frequent in females with obesity than in those without obesity, with Ala12Ala carriers having significantly higher weight and body mass index (BMI), however the association disappeared when adjusting by leptin concentrations. The Ala12Ala genotype was associated with significantly higher HDL-cholesterol and apoA-I levels in males but not in females, independently of BMI. In a recessive model, in females, leptin levels appeared higher in Ala12Ala carriers. Although no apparent differences were observed in any sex when analyzing insulin levels and HOMA among genotypes without adjusting, lower insulin levels and lower HOMA appeared associated with Ala12Ala carriers when adjusting for BMI and leptin levels. In summary, our data showed that leptin seems to be having an effect on the association between the PPARγ2 Pro12Ala and BMI. Besides, after controlling for BMI and leptin, a protective effect of the Ala12Ala variant of the PPARγ2 Pro12Ala polymorphism on insulin sensitivity is evident already in prepubertal children.

Diet and PPARG2 Pro12Ala Polymorphism Interactions in Relation to Cancer Risk: A Systematic Review.

Peroxisome proliferator-activated receptor-γ2 gene Pro12Ala allele polymorphism (PPARG2 Pro12Ala; rs1801282) has been linked to both cancer risk and dietary factors. We conducted the first systematic literature review of studies published before December 2020 using the PubMed database to summarize the current evidence on whether dietary factors for cancer may differ by individuals carrying C (common) and/or G (minor) alleles of the PPARG2 Pro12Ala allele polymorphism. The inclusion criteria were observational studies that investigated the association between food or nutrient consumption and risk of incident cancer stratified by PPARG2 Pro12Ala allele polymorphism. From 3815 identified abstracts, nine articles (18,268 participants and 4780 cancer cases) covering three cancer sites (i.e., colon/rectum, prostate, and breast) were included. CG/GG allele carriers were more impacted by dietary factors than CC allele carriers. High levels of protective factors (e.g., carotenoids and prudent dietary patterns) were associated with a lower cancer risk, and high levels of risk factors (e.g., alcohol and refined grains) were associated with a higher cancer risk. In contrast, both CG/GG and CC allele carriers were similarly impacted by dietary fats, well-known PPAR-γ agonists. These findings highlight the complex relation between PPARG2 Pro12Ala allele polymorphism, dietary factors, and cancer risk, which warrant further investigation.

Molecular & biochemical analysis of Pro12Ala variant of PPAR-γ2 gene in type 2 diabetes mellitus.

Diabetes has emerged as a major threat to human life globally. Genomic studies have found a significant link between the Pro12Ala polymorphism of the PPAR-γ2 gene with incidence as well as occurrence of the risk of metabolic syndrome. The present study was aimed at assessing the PPAR-γ2 variant in an Asian Indian cohort of type 2 diabetes patients and its correlation with metabolic parameters. The present case-control study involved 100 type 2 diabetic patients and 100 asymptomatic healthy volunteers enrolled in random. Assessment of demographic factors and biochemical parameters were done for all enrolled. In addition, genotyping for the Pro12Ala (CCA to GCA) polymorphism was done by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) technology. The genotyping study detected the frequency of the CC genotype (Pro12Pro) to be higher in frequency in comparison to the heterozygous CG genotype in both, cases and controls. The homozygous GG genotype (Ala12Ala) was not detected in any of the cases or controls assessed. Biochemical analysis of the levels of malondialdehyde (MDA) detected a significant increase (p < 0.0001). Additionally, increase in levels of fasting and postprandial glucose, total cholesterol, triglycerides, and parameters of the liver and renal function tests were detected. This study detected the PPAR-γ2 to be a significant biomarker for type 2 diabetes mellitus.

Pro12Ala PPAR-γ2 and +294T/C PPAR-δ Polymorphisms and Association with Metabolic Traits in Teenagers from Northern Mexico.

Peroxisome proliferator-activated receptors (PPARs) play roles in glucose and lipid metabolism regulation. Pro12Ala PPAR-γ2 and +294T/C PPAR-δ have been associated with dyslipidemia, hyperglycemia and high body mass index (BMI). We compared metabolic traits and determined associations with Pro12Ala PPAR-γ2 or +294T/C PPAR-δ polymorphism among teenagers from different ethnicity. Four hundred and twelve samples with previous biochemical and biometric measurements were used. Genomic DNA from peripheral blood was extracted and analyzed by end-point PCR for Pro12Ala PPAR-γ2. The +294T/C PPAR-δ PCR product was also digested with Bsl I. Two genotype groups were formed: major allele homozygous and minor allele carriers. Pro12Ala PPAR-γ2 G minor allele frequencies were: 10% in Mestizo-1, 19% in Mestizo-2, 23% in Tarahumara, 12% in Mennonite, and 17% in the total studied population. The +294T/C PPAR-δ C minor allele frequencies were: 18% in Mestizo-1, 20% in Mestizo-2, 6% in Tarahumara, 13% in Mennonite, and 12% in the total studied population. Teenagers with PPAR-γ2 G allele showed a greater risk for either high waist/height ratio or low high-density lipoprotein; and, also had lower total cholesterol. Whereas, PPAR-γ2 G allele showed lower overweight/obesity phenotype (BMI Z-score) frequency, PPAR-δ C allele was a risk factor for it. Metabolic traits were associated with both PPAR polymorphisms.

Effects Of PPARγ2 Pro12Ala Variant On Adipocyte Phenotype Dependent Of DHA.

BACKGROUND: Peroxisome proliferator-activated receptor γ2 (PPARγ2) plays a critical role in the regulation of adipocyte differentiation and adipocytokine production. The Pro12Ala variant is the most common mutation in the PPARγ2 gene. Its effect appears to be sensitive to dietary factors, such as docosahexaenoic acid (DHA) level. The purpose of this study was to investigate the interaction effect between PPARγ2 Pro12Ala variant and DHA on the phenotypes of adipocytes. METHODS: We generated stable 3T3-L1 cell lines expressing wild-type PPARγ2 or PPARγ2 Pro12Ala variant. These two cell lines were cultured with different concentrations of DHA (0, 50, 200 umol/L). Then Oil red O staining was used to observe cell differentiation and the degree of lipid accumulation, TUNNEL assay was used to detect cell apoptosis, and ELISA assays were used to detect the changes of TNF-α, resistin and adiponectin levels in cell culture supernatant. RESULTS: PPARγ2 Pro12Ala variant reduced lipid droplet accumulation in 3T3-L1 preadipocytes treated with or without 50 µmol/L DHA, but not with 200 µmol/L DHA, compared to that of wild-type PPARγ2. PPARγ2 reduced resistin production and increased adiponectin production in 3T3-L1 adipocytes, whereas PPARγ2 Pro12Ala variant diminished these effects. However, the absence of DHA blocked PPARγ2 Ala12 variant-induced effects on adiponectin production. There was no significant difference in TNF-α secretion between wild-type PPARγ2 and PPARγ2 Pro12Ala cells whether with or without DHA. CONCLUSION: These results indicated that the effects of PPARγ2 Pro12Ala variant were dependent on DHA concentration.

Association of PPARG Gene Polymorphisms Pro12Ala with Type 2 Diabetes Mellitus: A Meta-analysis.

BACKGROUND: Previous studies suggested that the single nucleotide polymorphisms of Pro12Ala located within the PPARG gene were significantly associated with the T2DM. Recently, the genetic studies on Pro12Ala were conducted in the different ethnic groups and the results of each study were shown to be inconsistent. Moreover, the systematic review has not been updated since 2000. OBJECTIVE: To further validate the risk of Pro12Ala for T2DM disease based on the genetic data. METHODS: The genetic studies on the Pro12Ala in the T2DM were searched in the PubMed and PMC database from January 2000 to October 2017. The meta-analysis was conducted with the CMA software. RESULTS: The meta-analysis collected 14 studies including 20702 cases and 36227 controls. The combined analysis of all studies found that Pro12Ala was shown to be significantly associated with T2DM and the Ala allele played the increasing risks for the disease. Nevertheless, publication bias was detected in the combined analysis. The subgroup analysis indicated that Pro12Ala was found to be significant in the Caucasian and Chinese population. There was no heterogeneity and publication bias in these two groups. CONCLUSION: The meta-analysis confirmed the evidence that the Pro12Ala was the susceptible variant for the decreasing risks for the T2DM.

Is the rs1801282 (G/C) Polymorphism of PPAR - Gamma Gene Associated with T2DM in Iraqi People?

BACKGROUND: Pro12Ala (rs1801282) is a common polymorphism of the human PPAR-γ gene. Studies have demonstrated conflicting results about its association with T2DM worldwide. There are no reports about such possible association among Iraqi people. OBJECTIVES: This study aims at finding out whether having the mutant allele (Ala12) might be associated with T2DM among Iraqi people. METHODS: One hundred and ninety-two Arabic Iraqi adult subjects (97 with T2DM and 95 controls) were genotyped using PCR- RFLP. Clinical, anthropometrical and biochemical variables were compared regarding the Pro12Ala genotypes. RESULTS: About 5.67% of people with diabetes were carriers of the (Ala12) allele versus 9.47% of controls. Allelic and genotypic frequencies were not statistically different among diabetics and controls [(χ2= 1.99, p= 0.16) and (χ2= 2.17, p= 0.14)]. Age, BMI and smoking- but not Pro12Ala - were independent risk factors for T2DM in our subjects. Pro12Ala was not associated with T2DM (Odd's ratio 0.55, 95% CI 0.23- 1.32, p= 0.14). CONCLUSIONS: Our study revealed a relatively high frequency of the Ala12 allele among Arabic Iraqis. These frequencies did not significantly differ between diabetics and controls indicating the absence of association of Pro12Ala with T2DM among Iraqis.

Assessment of the Pro12Ala Polymorphism in the PPAR-γ2 Gene among Type 2 Diabetes Patients in a Nigerian Population.

The association between the Pro12Ala polymorphism of the PPARγ2 gene, type 2 diabetes (T2D), and obesity in certain ethnic populations has been reported. However, this relationship has not yet been described among diabetes patients in Nigeria. This study investigated the relationship between the Pro12Ala polymorphism in the PPARγ2 gene, obesity, and lipid abnormalities characterizing T2D among patients in Nigeria. This case-control study recruited 73 T2D and 75 non-diabetic (ND) patients. Demographic and clinical data were collected and blood glucose levels together with serum lipid profile for patients were measured. Pro12Ala polymorphism in the PPARγ2 gene was genotyped by restriction fragment length-Polymerase Chain Reaction (RFLP-PCR). The PPAR-γ2 gene (amplicon size = 270 base pair) was successfully amplified for all samples. Following restriction enzyme digestion and analysis by agarose gel electrophoresis, amplicons from samples showed a band of size 270 bp and were of the wild homozygous Pro/Pro genotype. Ala12 variant was totally absent from the study population. Obesity, estimated using Body Mass Index (BMI) and waist circumference (WC), was significantly higher (p < 0.05) in T2D patients compared to the non-diabetic patients. More so, the prevalence of lipid abnormalities; hypercholesterolaemia (TC > 200 mg/dL), hypertriglyceridaemia (TG > 150 mg/dL), high HDL (>100 mg/dL), and low HDL (<50 mg/dL) was significantly greater (p < 0.001) in T2D patients compared to non-diabetic patients. Results obtained further indicated lack of significant association between PPAR-γ2 gene polymorphism, T2D, and obesity. However, obesity and dyslipidaemia were strongly associated in T2D patients.