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G Allele of the rs1801282 Polymorphism in PPARγ Gene Confers an Increased Risk of Obesity and Hypercholesterolemia, While T Allele of the rs3856806 Polymorphism Displays a Protective Role Against Dyslipidemia: A Systematic Review and Meta-Analysis.
Li, S, He, C, Nie, H, Pang, Q, Wang, R, Zeng, Z, Song, Y
Frontiers in endocrinology. 2022;:919087
Abstract
BACKGROUND The relationships between the rs1801282 and rs3856806 polymorphisms in nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) gene and obesity indexes as well as serum lipid levels have been extensively investigated in various studies, but the results were inconsistent and even contradictory. METHODS PubMed, Google Scholar, Embase, Cochrane Library, Web of Science, Wanfang, CNKI and VIP databases were searched for eligible studies. The random-effTPDEects model was used, and standardized mean difference (SMD) with 95% confidence interval (CI) was calculated to estimate the differences in obesity indexes and serum lipid levels between the subjects with different genotypes in a dominant model. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. RESULTS One hundred and twenty studies (70,317 subjects) and 33 studies (18,353 subjects) were identified in the analyses for the rs1801282 and rs3856806 polymorphisms, respectively. The G allele carriers of the rs1801282 polymorphism had higher levels of body mass index (SMD = 0.08 kg/m2, 95% CI = 0.04 to 0.12 kg/m2, p < 0.001), waist circumference (SMD = 0.12 cm, 95% CI = 0.06 to 0.18 cm, p < 0.001) and total cholesterol (SMD = 0.07 mmol/L, 95% CI = 0.02 to 0.11 mmol/L, p < 0.01) than the CC homozygotes. The T allele carriers of the rs3856806 polymorphism had lower levels of low-density lipoprotein cholesterol (SMD = -0.09 mmol/L, 95% CI = -0.15 to -0.03 mmol/L, p < 0.01) and higher levels of high-density lipoprotein cholesterol (SMD = 0.06 mmol/L, 95% CI = 0.02 to 0.10 mmol/L, p < 0.01) than the CC homozygotes. CONCLUSIONS The meta-analysis suggests that the G allele of the rs1801282 polymorphism confers an increased risk of obesity and hypercholesterolemia, while the T allele of the rs3856806 polymorphism displays a protective role against dyslipidemia, which can partly explain the associations between these polymorphisms and cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier [CRD42022319347].
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Association between PPAR-γ2 gene polymorphisms and diabetic retinopathy risk: a meta-analysis.
Li, XF, Jiang, GB, Cheng, SY, Song, YF, Deng, C, Niu, YM, Cai, JW
Aging. 2021;(4):5136-5149
Abstract
A close association between peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) and the development of diabetic retinopathy (DR) has been previously suggested. Herein, a meta-analysis was conducted to explore the association between PPAR-γ2 polymorphisms and DR risk by performing a systematic search and quantitative analysis. Overall, fourteen articles involving 10,527 subjects were included. The pooled results did not reveal an association between PPAR-γ2 rs1801282 C/G and DR susceptibility in the overall population (e.g., the dominant model: CG+GG vs. CC, OR=0.85, 95% CI=0.69-1.06, P=0.15, I2=62.9%). Furthermore, heterogeneity tests, cumulative analyses, sensitivity analyses, and publication bias analyses were conducted and showed that the results were robust. Similarly, race-based subgroup analyses and other subgroup analyses did not reveal an association between the rs1801282 C/G and DR susceptibility. In addition, no significant association was observed between PPAR-γ2 rs3856806 C/T polymorphism and DR risk (e.g., the dominant model: CT+TT vs. CC, OR=1.12, 95%CI=0.91-1.37, P=0.28, I2=27.0%). Overall, based on the current sample size and the level of evidence presented in the study, the results suggest that PPAR-γ2 gene polymorphisms are not associated with DR risk.
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Cardiovascular Risk and Safety Evaluation of a Dual Peroxisome Proliferator-Activated Receptor-Alpha/Gamma Agonist, Aleglitazar, in Patients With Type 2 Diabetes: A Meta-analysis.
Han, CL, Qu, CZ
Journal of cardiovascular pharmacology. 2020;(4):351-357
Abstract
This study evaluates the cardiovascular risk and safety of a dual peroxisome proliferator-activated receptor alpha and gamma (PPARα&γ), aleglitazar, for the management of type 2 diabetes mellitus. Studies were identified after a literature search in electronic databases and included in the meta-analysis according to eligibility criteria. Meta-analyses of mean differences in the changes from the baseline or odds ratios of selected indices between the aleglitazar- and the placebo/comparator-treated participants were performed. Seven studies {11,832 individuals; age 59.3 years [95% confidence interval (CI) 56.4-61.9]; body mass index 30.8 kg/m [95% CI 30.1-31.7]; sex, 54% males [44-64]} were included. In comparison with the placebo or pioglitazone, the aleglitazar treatment significantly improved %HbA1c, high-density lipoprotein-cholesterol (HDL-chol), and triglycerides. Aleglitazar also significantly decreased fasting plasma glucose and apolipoprotein B compared with the placebo. However, compared with the placebo or pioglitazone, aleglitazar significantly increased serum creatinine levels and significantly decreased the estimated glomerular filtration rate. In addition, the aleglitazar treatment was associated with a significantly increased body weight. Incidence of hypoglycemia, gastrointestinal hemorrhage, bone fractures, heart failure, cardiovascular death, and malignancy was higher in the aleglitazar group. Despite efficacy in glycemic and lipidic control, the aleglitazar treatment was associated with a poor safety profile.
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Implications of critical PPARγ2, ADIPOQ and FTO gene polymorphisms in type 2 diabetes and obesity-mediated susceptibility to type 2 diabetes in an Indian population.
Phani, NM, Vohra, M, Rajesh, S, Adhikari, P, Nagri, SK, D'Souza, SC, Satyamoorthy, K, Rai, PS
Molecular genetics and genomics : MGG. 2016;(1):193-204
Abstract
Peroxisome proliferator-activated receptors (PPARγ), adiponectin (ADIPOQ) and fat mass and obesity-associated gene (FTO) have been reported as a key candidate genes for obesity, type 2 diabetes (T2D) susceptibility and insulin resistance, and we hypothesize that in the background of obesity, the effect of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) variant could potentially influence T2D susceptibility. To decipher a more accurate estimation toward its population-specific impact of these variants toward susceptibility to T2D, a case-control study, systematic review and a meta-analysis was performed in a South Asian population. A case-control analysis of 518 T2D cases and 518 controls of Karnataka origin were performed to analyze the association of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) on the risk of T2D. In addition, a systematic review and meta-analysis for PPARγ2 (rs1801282) and FTO (rs9939609) was elucidated from Asian population. Our investigation showed that PPARγ2 (rs1801282) and FTO (rs9939609) are associated with T2D susceptibility. When T2D cohort was further stratified according to the obesity status, PPARγ2 (rs1801282) and FTO (rs9939609) showed association with T2D only in the obese diabetic group and ADIPOQ (rs16861194) showed no difference in risk of susceptibility to the disease. The meta-analysis of PPARγ2 (rs1801282) showed population-specific association for T2D susceptibility as opposed to FTO (rs9939609) which showed no difference in population effect toward T2D susceptibility. In conclusion, our study showed that PPARγ2 (rs1801282) and FTO (rs9939609) variants are associated with T2D susceptibility when associated with adiposity in Indian population.
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Effects of telmisartan on fat distribution: a meta-analysis of randomized controlled trials.
Choi, GJ, Kim, HM, Kang, H, Kim, J
Current medical research and opinion. 2016;(7):1303-9
Abstract
OBJECTIVES Several meta-analyses have confirmed the positive metabolic effects of telmisartan, an angiotensin II receptor blocker that can also act as a partial peroxisome proliferator-activated receptor-γ agonist, compared to those of other angiotensin II receptor blockers. These effects include decreased fasting glucose, glycosylated hemoglobin, interleukin-6, and tumor necrosis factor-α levels. However, no systemic analysis of telmisartan's effects on body fat distribution has been performed. We performed a meta-analysis of randomized controlled telmisartan trials to investigate its effects on body weight, fat distribution, and visceral adipose reduction. RESEARCH DESIGN AND METHODS A literature search was performed using Embase, MEDLINE, and the Cochrane Library between January 1966 and November 2013. Randomized controlled trials in English and meeting the following criterion were included: random assignment of hypertensive participants with overweight/obesity, metabolic syndrome, or glucose intolerance to telmisartan or control therapy group. RESULTS Of 651 potentially relevant reports, 15 satisfied the inclusion criterion. While visceral fat area was significantly lower in the telmisartan group than in the control group (weighted mean difference = -18.13 cm(2), 95% C.I. = -27.16 to -9.11, Pχ(2) = 0.19, I(2) = 41%), subcutaneous fat area was similar (weighted mean difference =2.94 cm(2), 95% C.I. = -13.01 to 18.89, Pχ(2) = 0.30, I(2) = 17%). Total cholesterol levels were significantly different between the groups (standardized mean difference = -0.24, 95% C.I. = -0.45 to -0.03, Pχ(2) = 0.0002, I(2) = 67%). LIMITATIONS Limitations include: (1) limited number of studies, especially those evaluating fat distribution; (2) different imaging modalities to assess visceral fat area (V.F.A.) and subcutaneous fat area (S.F.A.); (3) observed heterogeneity. CONCLUSION The findings suggest that telmisartan affected fat distribution, inducing visceral fat reduction, and thus could be useful in hypertensive patients with obesity/overweight, metabolic syndrome, or glucose intolerance.
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Association of the variants in the PPARG gene and serum lipid levels: a meta-analysis of 74 studies.
Li, Q, Chen, R, Bie, L, Zhao, D, Huang, C, Hong, J
Journal of cellular and molecular medicine. 2015;(1):198-209
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Abstract
Considerable studies have been carried out to investigate the relationship between the polymorphisms of PPARG (Pro12Ala, C161T and C1431T) and serum lipid levels, but the results were inconclusive. Hence, we conducted a meta-analysis to clarify the association. MEDLINE, EMBASE and the Cochrane Library databases were searched systematically. The subgroup analysis was performed based on ethnicity. Seventy-four studies with 54,953 subjects were included in this meta-analysis. In Pro12Ala, the group with the 'PP' (C/C genotype) genotype group had lower levels of total cholesterol (TC) (mean difference, MD: -0.02, P < 0.00001; I(2) = 28%), low-density lipoprotein cholesterol (LDL-C) (MD: -0.02, P < 0.00001; I(2) = 30%) and higher levels of triglyceride (TG) (MD: 0.06, P < 0.00001; I(2) = 30%) than the combined 'PA+AA' (PA = C/G genotype, AA = G/G genotype) genotype group in Asian population, and the group with the 'PP' genotype had higher levels of TG (MD: 0.07, P < 0.02; I(2) = 67%) than the combined 'PA+AA' genotype group in non-Asian population. No statistically significant differences in the levels of TC, TG, high-density lipoprotein cholesterol, LDL-C were detected between different genotypes in C161T(Asian or non-Asian) and C1431T(Asian) polymorphisms. This meta-analysis was a renewed and confirmed study to assess the association between PPARG polymorphisms and serum lipid levels in Asian and non-Asian populations. There is a prominent association between Pro12Ala polymorphism and the levels of TC, LDL-C and TG in Asian population. No statistically significant differences in serum lipid levels were detected between different genotypes in C161T and C1431T polymorphisms.
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Obesity and Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor-Gamma Gene in Healthy Adults: A Systematic Review and Meta-Analysis.
Mansoori, A, Amini, M, Kolahdooz, F, Seyedrezazadeh, E
Annals of nutrition & metabolism. 2015;(2):104-18
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Abstract
BACKGROUND The aim of this systematic review was to evaluate the relationship between obesity and peroxisome proliferator-activated receptor-gamma (PPARx03B3;) Pro12Ala polymorphism in healthy adults. SUMMARY Weighted mean differences (WMDs) of body mass index (BMI) were calculated for different inheritance models and subgroups. Fifty-six studies were eligible for inclusion in the meta-analysis. The result shows that the Ala allele of this polymorphism was associated with increased WMD in mean BMI (WMD = 0.29, 95% CI 0.10-0.48, p = 0.003). The Ala carriers were associated with increased WMD in mean BMI values in both genders and in the Caucasian subgroup. The associations were seen among people with higher levels of BMI (BMI ≥35). MESSAGE The Ala allele of the PPARx03B3; Pro12Ala polymorphism in healthy adults was associated with increased BMI under a dominant model of inheritance.
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PPARγ Pro12Ala and His447His polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis.
Lee, YH, Song, GG
Genetics and molecular research : GMR. 2015;(2):7248-57
Abstract
We investigated whether Pro12Ala (C→G) and His447His (C→T) polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARγ) gene are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the PPARγ Pro12Ala and His447His polymorphisms and AD in subjects. The meta-analysis was performed according to the apolipoprotein E (APOE) ɛ4 allele status. A total of eight studies were considered in our meta-analysis, comprising 2948 patients with AD and 3753 controls. Meta-analysis showed no association between AD and the PPARγ Pro12Ala G allele in any of the study subjects [odds ratio (OR) = 1.013, 95% confidence interval (95%CI) = 0.906-1.132, P = 0.821] or in the European and Asian populations (OR = 0.997, 95%CI = 0.890-1.118, P = 0.965; OR = 1.409, 95%CI = 0.832-2.387, P = 0.202, respectively). We tested whether the APOE ɛ4 allele affects the association between the PPARγ Pro12Ala polymorphism and AD. Meta-analysis showed no association between AD and the PPARγ G allele in any of the study subjects with or without the APOE ɛ4 allele. Meta-analysis showed no association between AD and the PPARγ His447His T allele in the European population (OR for T allele = 0.912, 95%CI = 0.732-1.136, P = 0.409). This meta-analysis has shown that there is a lack of association between the PPARγ Pro12Ala and His447His polymorphisms and AD risk.
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Association of the PPARγ2 Pro12Ala polymorphism with increased risk of cardiovascular diseases.
Li, Y, Zhu, J, Ding, JQ
Genetics and molecular research : GMR. 2015;(4):18662-74
Abstract
This meta-analysis investigated the correlation between the PPARγ2 Pro12Ala polymorphism and cardiovascular disease (CVD). Electronic database and manual searches were conducted to retrieve studies published relevant to the PPARγ2 Pro12Ala polymorphism and CVD. Rigorous inclusion and exclusion criteria were employed for selection of high-quality patients-control studies. Statistical data analyses on allelic, dominant, homozygous, heterozygous, and recessive inheritance models were performed using the R 3.1.0 and Stata 12.0 software. We enrolled 12 case-control studies consisting of 10,189 patients with CVD [1070 with myocardial infarction (MI), 7849 with coronary artery disease (CAD), and 1270 with acute coronary syndromes (ACS)] and 17,899 controls. The results of meta-analyses revealed that the PPARγ2 Pro12Ala (rs1801282) polymorphism was correlated with a higher risk of CVD under both allelic and dominant models, while no statistical significance was found under homozygous, heterozygous, or recessive models. Subgroup analysis based on disease showed that the PPARγ2 Pro12Ala (rs1801282) polymorphism was correlated with a higher risk of MI under both allelic and dominant models, while no statistical significance was found for association with CAD or ACS under allele or dominant models. Furthermore, under homozygous, heterozygous, and recessive models, the PPARγ2 Pro12Ala (rs1801282) polymorphism had no statistically significant association with MI, CAD, or ACS. The results of this meta-analysis suggest that the PPARγ2 Pro12Ala (rs1801282) polymorphism might be correlated with a higher risk of CVD, particularly MI, and could serve as an important early indicator for CVD.
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Effects of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ2 gene on metabolic syndrome risk: a meta-analysis.
Zhang, R, Wang, J, Yang, R, Sun, J, Chen, R, Luo, H, Liu, D, Cai, D
Gene. 2014;(1):79-87
Abstract
BACKGROUND Associations between peroxisome proliferator-activated receptor γ2 (PPARγ2) gene polymorphism and metabolic syndrome risk remained controversial and ambiguous. Thus, we performed a meta-analysis to assess the association between Pro12Ala polymorphism in PPARγ2 gene and metabolic syndrome susceptibility. METHODS An electronic literature search was conducted on Medline, OVID, Cochrane Library database, and the China National Knowledge Internet up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the fixed or random effects model. RESULTS Ten studies involving a total of 4456 cases and 10343 controls were included in this meta-analysis. No statistical evidence of association was found between Pro12Ala polymorphism and metabolic syndrome risk in all genetic models (homozygote model: OR=0.83, 95% CI=0.62-1.12; heterozygote model: OR=1.04, 95% CI=0.94-1.14; dominant model: OR=1.02, 95% CI=0.93-1.12; recessive model: OR=0.83, 95% CI=0.62-1.11). No statistical evidence of significant association was observed when stratified by ethnicity, definition of metabolic syndrome, source of control groups and quality score of the selected articles. All in all, the results did not support a major role of the Pro12Ala variant of the PPARγ2 gene in metabolic syndrome risk. CONCLUSIONS This meta-analysis suggested that the effect of Pro12Ala polymorphism in PPARγ2 gene may not be related to metabolic syndrome as an entity. However, Pro12Ala may affect the single component of metabolic syndrome. A large, well designed study is required to more adequately assess the role for Pro12Ala polymorphism on metabolic syndrome.