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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Rana S, Ali S, Wani HA, Mushtaq QD, Sharma S, Rehman MU. Metabolic syndrome and underlying genetic determinants-A systematic review. J Diabetes Metab Disord 2022; 21:1095-1104. [PMID: 35673448 PMCID: PMC9167205 DOI: 10.1007/s40200-022-01009-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/13/2022] [Indexed: 12/18/2022]
Abstract
The metabolic syndrome is a cluster of heritable and related traits which has been associated with a range of pathophysiological factors including dyslipidaemia, abdominal obesity, increased fasting plasma glucose (FPG) and hypertension. The documented genetic basis of the metabolic syndrome include several chromosomal positions, numerous candidate gene-associated polymorphisms, different genetic variants, which are linked to the syndrome either as a trait or entities mainly linked to metabolic process. Additionally, the latest findings related to the contribution of epigenetic mechanisms, microRNAs, sporadic variants, non-coding RNAs, and assessing the role of genes in molecular systems has enhanced our understanding of the syndrome. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Nonetheless, a common shared genetic cause has not been established to clarify the coexistence of their components and further investigation is required. While mostly neglected and rarely known, hereditary predisposition needs to be studied, including with the current defective phenotypic condition descriptions. Metabolic syndrome is a multi-faceted characteristic with abundant properties and the condition can arise from interactions between environmental variables such as physical inactivity, caloric obesity and genetic susceptibility. Although there is support for genetic determinants from family and twin research, there is still no recognised genomic DNA marker for genetic association and linkages with quite a long way off potential for clinical application. In the present review efforts have been made to through light on the various genetic determinants with large effects that underlie with the association of these traits to this syndrome. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits.
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Affiliation(s)
- Sanjeev Rana
- grid.440710.60000 0004 1756 649XHuman Genomics Research Group, Shri Mata Vaishno Devi University (SMVDU), Katra, J and K India
| | - Shafat Ali
- grid.412997.00000 0001 2294 5433Cytogenetics and Molecular Biology Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, J and K India
| | - Hilal Ahmad Wani
- grid.412997.00000 0001 2294 5433Department of Biochemistry, Government Degree College Sumbal, Bandipora, J and K India
| | | | - Swarkar Sharma
- grid.440710.60000 0004 1756 649XHuman Genomics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University (SMVDU), Katra, J and K India
| | - Muneeb U Rehman
- grid.56302.320000 0004 1773 5396College of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Li S, He C, Nie H, Pang Q, Wang R, Zeng Z, Song Y. 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. Front Endocrinol (Lausanne) 2022; 13:919087. [PMID: 35846293 PMCID: PMC9276935 DOI: 10.3389/fendo.2022.919087] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
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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Affiliation(s)
- Shujin Li
- Central Laboratory, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu, China
| | - Chuan He
- Department of Cardiology, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu, China
| | - Haiyan Nie
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Qianyin Pang
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Ruixia Wang
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Zhifu Zeng
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Yongyan Song
- Central Laboratory, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu, China
- *Correspondence: Yongyan Song,
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Jonas K, Magoń W, Podolec P, Kopeć G. Triglyceride-to-High-Density Lipoprotein Cholesterol Ratio and Systemic Inflammation in Patients with Idiopathic Pulmonary Arterial Hypertension. Med Sci Monit 2019; 25:746-753. [PMID: 30683836 PMCID: PMC6359883 DOI: 10.12659/msm.912766] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background Idiopathic pulmonary arterial hypertension (IPAH) patients are characterized by elevated triglyceride (TG)-to-HDL cholesterol (HDL-C) ratio, which has been proposed to be an important prognostic factor in this population. The mechanism of this phenomenon remains unknown. We therefore investigated the potential determinants of increased TG/HDL-C ratio in IPAH patients. Material/Methods We prospectively recruited consecutive clinically stable IPAH patients between January 2016 and February 2017. Patients with diabetes or using statins were excluded. Anthropometric measurements included body mass index (BMI) and skinfold thickness; body fat mass was calculated using age and sex-specific equations. We assessed lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR), serum adipokine levels (adiponectin, resistin, leptin, and visfatin), and circulating cytokines (IL-1β, IL-6, MCP-1, and TNF-α). Results We assessed 47 IPAH patients: 9 of them had been diagnosed with diabetes and 10 were treated with statins; therefore, were excluded them from further analysis. Age, sex distribution, and BMI were similar irrespectively of TG/HDL-C ratio. Patients with increased TG/HDL-C ratio (>3) as compared to patients with TG/HDL-C ≤3 were characterized by higher levels of IL-1β, MCP-1, and IL-6. TG level was correlated with IL-1β (R=0.76, p<0.001), IL-6 (R=0.52, p=0.005), TNF-α (R=0.62, p<0.001), and MCP-1 (R=0.63, p<0.001). IL-1β was also inversely correlated with HDL-C (R=−0.44, p=0.02). We found no differences in concentration of fasting glucose, insulin, HOMA-IR, body fat content, or adipokine levels between patients with higher and lower TG/HDL-C ratios. Conclusions In IPAH patients, elevated TG/HDL-C ratio is a marker of systemic inflammation.
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Affiliation(s)
- Kamil Jonas
- Department of Cardiac and Vascular Diseases, Faculty of Medicine, Jagiellonian University Medical College, John Paul II Hospital in Cracow, Cracow, Poland
| | - Wojciech Magoń
- Department of Cardiac and Vascular Diseases, Faculty of Medicine, Jagiellonian University Medical College, John Paul II Hospital in Cracow, Cracow, Poland
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Faculty of Medicine, Jagiellonian University Medical College, John Paul II Hospital in Cracow, Cracow, Poland
| | - Grzegorz Kopeć
- Department of Cardiac and Vascular Diseases, Faculty of Medicine, Jagiellonian University Medical College, John Paul II Hospital in Cracow, Cracow, Poland
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Sözen M, Özcan M, Çıldır M, Doğru I, Aygök A, Balkan K. ASSOCIATION OF THE HUMAN PPARγ2 PRO12ALA POLYMORPHISM WITH OBESITY IN A POPULATION FROM TURKEY. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2018; 14:459-465. [PMID: 31149297 PMCID: PMC6516403 DOI: 10.4183/aeb.2018.459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND There have been a number of reports on the relationship between the PPARγ2 Pro12Ala genotype and the development of obesity. OBJECTIVE A case-control survey was designed to investigate the potential association between a Pro12Ala polymorphism in the PPARγ2 gene and obesity and/or obesity-related phenotypes in a population from Turkey. MATERIALS AND METHODS The polymerase chain reaction and restriction enzyme digestion were used to genotype the Pro12Ala polymorphism of the PPARγ2 gene in 149 unrelated obese and 105 non-obese control subjects from Turkey. The data were analyzed statistically. RESULTS We found that the overall minor allele frequency was 0.12 in cases and 0.095 in controls. In terms of genotype distribution and allele frequencies among the cases versus controls in the population studied, only the gender-stratified analysis revealed a significantly higher frequency of Pro/Ala genotype within males. The polymorphism was associated with significantly higher weight, height, waist circumference, central adiposity (waist-to-hip ratio, WHR), lean body weight as well as dry body weight, but not overall adiposity (total body fat percentage, TBF) in cases carrying Ala allele (Pro/Ala or Ala/Ala). However, in the subjects carrying Ala allele of the control group, WHR values were found significantly lower. CONCLUSION Our results showed that the Pro12Ala polymorphism in the PPARγ2 gene is associated with obesity in the studied adult population from Turkey. These data suggest that the Pro12Ala polymorphism in PPARγ2 may be a potential genetic risk factor for central obesity.
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Affiliation(s)
- M.A. Sözen
- Med Biology, School of Medicine, Afyonkarahisar, Turkey
| | - M.U. Özcan
- Afyon Kocatepe University, School of Medicine, Afyonkarahisar, Turkey
| | - M. Çıldır
- Afyon Kocatepe University, School of Medicine, Afyonkarahisar, Turkey
| | - I.H. Doğru
- Afyon Kocatepe University, School of Medicine, Afyonkarahisar, Turkey
| | - A.G. Aygök
- Afyon Kocatepe University, School of Medicine, Afyonkarahisar, Turkey
| | - K.Ü. Balkan
- Afyon Kocatepe University, School of Medicine, Afyonkarahisar, Turkey
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Rocha RM, Barra GB, Rosa ÉCCC, Garcia ÉC, Amato AA, Azevedo MF. Prevalence of the rs1801282 single nucleotide polymorphism of the PPARG gene in patients with metabolic syndrome. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2017; 59:297-302. [PMID: 26331316 DOI: 10.1590/2359-3997000000086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 01/12/2015] [Indexed: 11/21/2022]
Abstract
OBJECTIVE This study aimed to get the genotypic and allelic frequencies of rs1801282 in 179 volunteer donors and 154 patients with Metabolic syndrome (MetS) in Brasilia, Brazil and also examine the association with anthropometric, biochemical and hemodynamic variables in the latter group. MetS comprises a group of diseases resulting from insulin resistance, in-creased risk of type 2 diabetes and atherosclerotic cardiovascular disease. MetS is defined by the presence of increased visceral fat, atherogenic dyslipidemia (elevated triglycerides (TGL)), with decreased high density lipoprotein (HDL) and increased low density lipoprotein (LDL) levels, hypertension (BPH) and disturbances in glucose homeostasis representing a significant burden across the world due to the alarming increase in the incidence over the last decades besides their significant morbidity and mortality. Peroxisome proliferator activated receptor-gamma (PPARg) has been mentioned as a candidate gene for determining the risk of MetS. It is a member of the nuclear receptors superfamily and a ligand-activated transcription factor, which regulates the expression of genes involved in the network lipogenesis and adipogenesis, insulin sensitivity, energy balance, inflammation, angiogenesis and atherosclerosis. Among the PPARG genetic variants, single nucleotide polymorphism rs1801282 has been the most extensively studied one since it was first described by Yen and cols. in 1997. This polymorphism is characterized by the replacement of a proline (CCC) to an alanine (GCA) at codon 12 of exon B, due to the exchange of a cytosine with a guanine. The Ala allele frequency varies in different ethnic groups. MATERIALS AND METHODS DNA was extracted using Chelex-100 method and determinations of genotypes were performed by allele-specific chain reaction. RESULTS The distribution of genotype frequency of the MetS group was not statistically different from the frequency in the donor population at large. In the first group, genotype frequency was CC to 0.869 and 0.103 for CG, while allelic frequencies were 0.948 for C and 0.052 for G allele. In the group of donors, the genotype and allele frequencies were 0.882 for CC, 0.117 to CG; and 0.941 to 0.059 for G and C, respectively. GG genotype was not found in any of the two groups. The genotype distribution and allele frequencies were in Hardy-Weinberg equilibrium. No marker could be detected from the analysis of anthropometric, biochemical and hemodynamic variables in the MetS group. CONCLUSION Our data suggest that this polymorphism is not correlated with predisposition to MetS. The results obtained on a small sample of the population of Brasilia, corroborate the data reported in the literature on the prevalence of this polymorphism in PPAR in populations of different ethnic origins.
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Amrita J, Mahajan M, Bhanwer A, Mohan G, Matharoo K. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Pro12Ala Gene Polymorphism and Oxidative Stress in Menopausal Women with Cardiovascular Disease from North Indian Population of Punjab. INT J HUM GENET 2017. [DOI: 10.1080/09723757.2017.1317106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Jyot Amrita
- Department of Biochemistry, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar 143 006, Punjab, India
| | - Mridula Mahajan
- Department of Biochemistry, Government Medical College, Amritsar 143 001, Punjab, India
| | - A.J.S. Bhanwer
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
| | - Gurinder Mohan
- Department of Medicine, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar 143 006, Punjab, India
| | - Kawaljit Matharoo
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
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Paramasivam D, Safi SZ, Qvist R, Abidin IBZ, Hairi NNM, Chinna K. Role of PPARG (Pro12Ala) in Malaysian type 2 diabetes mellitus patients. Int J Diabetes Dev Ctries 2016; 36:449-456. [DOI: 10.1007/s13410-015-0462-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Saleh R, Zahid ZI, Rahman MA, Jain P, Alam A, Kawaichi M, Reza HM. Prevalence of PPAR-γ2 (rs1801282), RETN (rs3745367) and ADIPOQ (rs2241766) SNP markers in the Bangladeshi type 2 diabetic population. Meta Gene 2016. [DOI: 10.1016/j.mgene.2016.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Nutrigenomic Functions of PPARs in Obesogenic Environments. PPAR Res 2016; 2016:4794576. [PMID: 28042289 PMCID: PMC5155092 DOI: 10.1155/2016/4794576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 10/03/2016] [Indexed: 12/26/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities.
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Chia PP, Fan SH, Say YH. Screening of Peroxisome Proliferator-Activated Receptors (PPARs) α, γ and α Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-Ethnic Malaysian Population. Ethn Dis 2015; 25:383-90. [PMID: 26673968 DOI: 10.18865/ed.25.4.383] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the association of peroxisome proliferator-activated receptor (PPAR) genes PPARα L162V, PPARγ2 C161T and PPARδ T294C single nucleotide polymorphisms (SNPs) with obesity and metabolic syndrome (Met-S) in a multi-ethnic population in Kampar, Malaysia. METHODS Socio-demographic data, anthropometric and biochemical measurements (plasma lipid profile, adiponectin and interleukin-6 [IL-6] levels) were taken from 307 participants (124 males; 180 obese; 249 Met-S; 97 Malays, 85 ethnic Chinese, 55 ethnic Indians). RESULTS The overall minor allele frequencies were .08, .22 and .30 for PPAR α L162V, γ C161T, δ T294C, respectively. All SNPs were not associated with obesity, Met-S and obesity with/without Met-S by χ(2) analysis, ethnicity-stratified and logistic regression analyses. Nevertheless, participants with V162 allele of PPARα had significantly higher IL-6, while those with T161 allele of PPARγ2 had significantly lower HOMA-IR. CONCLUSIONS All PPAR SNPs were not associated with obesity and Met-S in the suburban population of Kampar, Malaysia, where only PPARα V162 and PPARγ2 T161 alleles were associated with plasma IL-6 and HOMA-IR, respectively.
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Affiliation(s)
- Phee-Phee Chia
- 1. Department of Science and Engineering, Centre for Foundation Studies, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
| | - Sook-Ha Fan
- 2. Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
| | - Yee-How Say
- 2. Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
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Mansoori A, Amini M, Kolahdooz F, Seyedrezazadeh E. Obesity and Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor-Gamma Gene in Healthy Adults: A Systematic Review and Meta-Analysis. ANNALS OF NUTRITION AND METABOLISM 2015; 67:104-18. [PMID: 26361038 DOI: 10.1159/000439285] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 08/10/2015] [Indexed: 11/19/2022]
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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Affiliation(s)
- Anahita Mansoori
- Cellular and Molecular Nutrition Department, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran Iran
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Kim KC, Chun H, Lai C, Parnell LD, Jang Y, Lee J, Ordovas JM. The association between genetic variants of RUNX2, ADIPOQ and vertebral fracture in Korean postmenopausal women. J Bone Miner Metab 2015; 33:173-9. [PMID: 24570271 DOI: 10.1007/s00774-014-0570-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 01/16/2014] [Indexed: 01/10/2023]
Abstract
Contrary to the traditional belief that obesity acts as a protective factor for bone, recent epidemiologic studies have shown that body fat might be a risk factor for osteoporosis and bone fracture. Accordingly, we evaluated the association between the phenotypes of osteoporosis or vertebral fracture and variants of obesity-related genes, peroxisome proliferator-activated receptor-gamma (PPARG), runt-related transcription factor 2 (RUNX2), leptin receptor (LEPR), and adiponectin (ADIPOQ). In total, 907 postmenopausal healthy women, aged 60-79 years, were included in this study. BMD and biomarkers of bone health and adiposity were measured. We genotyped for four single nucleotide polymorphisms (SNPs) from four genes (PPARG, RUNX2, LEPR, ADIPOQ). A general linear model for continuous dependent variables and a logistic regression model for categorical dependent variables were used to analyze the statistical differences among genotype groups. Compared with the TT subjects at rs7771980 in RUNX2, C-carrier (TC + CC) subjects had a lower vertebral fracture risk after adjusting for age, smoking, alcohol, total calorie intake, total energy expenditure, total calcium intake, total fat intake, weight, body fat. Odds ratio (OR) and 95% interval (CI) for the vertebral fracture risk was 0.55 (95% CI 0.32-0.94). After adjusting for multiple variables, the prevalence of vertebral fracture was highest in GG subjects at rs1501299 in ADIPOQ (p = 0.0473). A high calcium intake (>1000 mg/day) contributed to a high bone mineral density (BMD) in GT + TT subjects at rs1501299 in ADIPOQ (p for interaction = 0.0295). Even if the mechanisms between obesity-related genes and bone health are not fully established, the results of our study revealed the association of certain SNPs from obesity-related genes with BMD or vertebral fracture risk in postmenopausal Korean women.
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Affiliation(s)
- Kyong-Chol Kim
- Department of Family Medicine, Chaum Hospital, Cha University, Seoul, Korea,
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Effect of the PPARγ C161T gene variant on serum lipids in ischemic stroke patients with and without type 2 diabetes mellitus. J Mol Neurosci 2014; 54:730-8. [PMID: 24841086 DOI: 10.1007/s12031-014-0326-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/06/2014] [Indexed: 12/17/2022]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in the regulation of lipid metabolism, diabetes, obesity, atherogenesis and inflammation. PPARγ genetic variation has been associated with metabolic and cardiovascular diseases. The aim of this study was to explore, for the first time, the relationship between PPARγ C161T polymorphism and the risk of ischemic stroke (IS) among patients with type 2 diabetes mellitus (T2DM). A total of 196 patients with IS (117 diabetics and 79 nondiabetics) and 192 controls were recruited to enroll in this study. PPARγ C161T genotyping was performed by PCR-RFLP technique. The 161T allele as compared with C allele was found to be higher in controls than in IS patients (with or without T2DM). After adjusting for multiple risk factors, the T allele carriers had significantly reduced IS risk (OR=0.575, 95% CI 0.348-0.951, p=0.030) compared to the CC homozygotes which increased significantly the risk in IS patients with T2DM (OR=1.85, 95% CI 1.23-2.62). Moreover, the triglycerides (TG) and ApoB levels in CC homozygote carriers were significantly higher than those in T allele carriers. These results indicate that the C161T of PPARγ may reduce the risk of IS by modulation of adipose metabolism especially TG and ApoB in IS patients with T2DM.
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El-Abhar HS, Schaalan MF. Phytotherapy in diabetes: Review on potential mechanistic perspectives. World J Diabetes 2014; 5:176-197. [PMID: 24748931 PMCID: PMC3990312 DOI: 10.4239/wjd.v5.i2.176] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 01/07/2014] [Accepted: 03/14/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM) is a widely spread epidemic disease that results from the absence of insulin, decreased secretion and/or impaired function. Since DM is a multi-factorial disease, the available pharmaceuticals, despite their sensible treatment, target mostly one pathway to control hyperglycemia and encounter several side effects. Therefore, new therapeutic paradigms aim to hit several pathways using only one agent. Traditionally, antidiabetic plants and/or their active constituents may fulfill this need. More than 200 species of plants possess antidiabetic properties which were evaluated mostly by screening tests without digging far for the exact mode of action. Searching among the different literature resources and various database and in view of the above aspects, the present article provides a comprehensive review on the available antidiabetic plants that have been approved by pharmacological and clinical evaluations, and which their mechanism(s) of action is assured. These plants are categorized according to their proved mode of action and are classified into those that act by inhibiting glucose absorption from intestine, increasing insulin secretion from the pancreas, inhibiting glucose production from hepatocytes, or enhancing glucose uptake by adipose and muscle tissues. The current review also highlights those that mimic in their action the new peptide analogs, such as exenatide, liraglutide and dipeptidylpeptidase-4 inhibitors that increase glucagon-like peptide-1 serum concentration and slow down the gastric emptying.
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Rooki H, Haerian MS, Azimzadeh P, Mirhafez R, Ebrahimi M, Ferns G, Ghayour-Mobarhan M, Zali MR. Associations between C1431T and Pro12Ala variants of PPARγ gene and their haplotypes with susceptibility to metabolic syndrome in an Iranian population. Mol Biol Rep 2014; 41:3127-33. [PMID: 24464185 DOI: 10.1007/s11033-014-3172-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 01/16/2014] [Indexed: 02/08/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that regulates a number of genes involved in lipid and carbohydrate metabolism. The aim of this study was to investigate the association of C1431T and Pro12Ala polymorphisms of PPARγ gene and their haplotypes and diplotypes with risk of metabolic syndrome (MetS) in an Iranian population. A total of 340 unrelated Iranian subjects, including 175 MetS patients and 165 normal controls were enrolled. Each group was then divided into two subgroups according to the genotype (Pro/Pro and Pro/Ala+Ala/Ala for Pro12Ala, CC and CT+TT for C1431T). Genotypes were determined using a TaqMan method. Anthropometric indices, fasting plasma glucose and fasting lipid profile were measured by routine methods. A significant difference in the frequencies of the C1431T genotypes was observed between MetS and control subjects (P=0.014), whereas no association was found for the Pro12Ala. The T allele carriers had a significantly increased risk of MetS compared to the CC genotype (P=0.016) even after correction for multiple-testing and adjustment for age, sex and genotype. The T allele may therefore be considered as a risk factor for MetS (P=0.003). Analysis of combined groups showed that X/Ala-CC and Pro/Pro-X/T diplotypes were associated with a higher body weight, waist circumference and waist to hip ratio among the individuals with MetS. Moreover the Ala-T haplotype was weakly associated with a higher level of triglyceride and lower level of HDL, suggesting the possibility of an interaction between Ala and T alleles. This study suggests that the PPARγ C1431T polymorphism is related to an increased risk of MetS in an Iranian population and interacts with the Pro12Ala polymorphism, further increasing the risk of MetS.
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Affiliation(s)
- Hassan Rooki
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,
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Vergotine Z, Kengne AP, Erasmus RT, Yako YY, Matsha TE. Rare mutations of peroxisome proliferator-activated receptor gamma: frequencies and relationship with insulin resistance and diabetes risk in the mixed ancestry population from South Africa. Int J Endocrinol 2014; 2014:187985. [PMID: 25197274 PMCID: PMC4150434 DOI: 10.1155/2014/187985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 07/16/2014] [Indexed: 11/17/2022] Open
Abstract
Background. Genetic variants in the nuclear transcription receptor, PPARG, are associated with cardiometabolic traits, but reports remain conflicting. We determined the frequency and the clinical relevance of PPARG SNPs in an African mixed ancestry population. Methods. In a cross-sectional study, 820 participants were genotyped for rs1800571, rs72551362, rs72551363, rs72551364, and rs3856806, using allele-specific TaqMan technology. The homeostatic model assessment of insulin (HOMA-IR), β-cells function (HOMA-B%), fasting insulin resistance index (FIRI), and the quantitative insulin-sensitivity check index (QUICKI) were calculated. Results. No sequence variants were found except for the rs3856806. The frequency of the PPARG-His447His variant was 23.8% in the overall population group, with no difference by diabetes status (P = 0.215). The His447His allele T was associated with none of the markers of insulin resistance overall and by diabetes status. In models adjusted for 2-hour insulin, the T allele was associated with lower prevalent diabetes risk (odds ratio 0.56 (95% CI 0.31-0.95)). Conclusion. Our study confirms the almost zero occurrences of known rare PPARG SNPs and has shown for the first time in an African population that one of the common SNPs, His447His, may be protective against type 2 diabetes.
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Affiliation(s)
- Z. Vergotine
- Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, P.O. Box 1906, Bellville, Cape Town 7530, South Africa
- Division of Chemical Pathology, Stellenbosch University, Cape Town 7505, South Africa
| | - A. P. Kengne
- Non-Communicable Diseases Research Unit, South African Medical Research Council and University of Cape Town, Cape Town 7505, South Africa
| | - R. T. Erasmus
- Division of Chemical Pathology, Stellenbosch University, Cape Town 7505, South Africa
| | - Y. Y. Yako
- Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, P.O. Box 1906, Bellville, Cape Town 7530, South Africa
| | - T. E. Matsha
- Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, P.O. Box 1906, Bellville, Cape Town 7530, South Africa
- *T. E. Matsha:
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Rooki H, Haerian MS, Azimzadeh P, Ebrahimi M, Mirhafez R, Ferns G, Ghayour-Mobarhan M, Zali MR. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population. INDIAN JOURNAL OF HUMAN GENETICS 2013; 19:423-9. [PMID: 24497707 PMCID: PMC3897137 DOI: 10.4103/0971-6866.124370] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. MATERIALS AND METHODS Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. RESULTS The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. CONCLUSIONS Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences.
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Affiliation(s)
- Hassan Rooki
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Monir-Sadat Haerian
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pedram Azimzadeh
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmoud Ebrahimi
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Mirhafez
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon Ferns
- Institute for Science and Technology in Medicine, University of Keele, Guy Hilton Research Centre, Thornburrow Drive, Stok on Trent, Staffordshire, United Kingdom
| | - Majid Ghayour-Mobarhan
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad-Reza Zali
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Motavallian A, Andalib S, Vaseghi G, Mirmohammad-Sadeghi H, Amini M. Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients. INDIAN JOURNAL OF HUMAN GENETICS 2013; 19:239-44. [PMID: 24019628 PMCID: PMC3758733 DOI: 10.4103/0971-6866.116126] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND: Peroxisome proliferator-activated receptor (PPARs) have been identified as ligand-activated transcription factors that belong to the nuclear receptor superfamily. It has been shown that an association exists between Proline 12 alanine (Pro12Ala) polymorphism of PPAR-GAMMA2 (PPAR-γ2) gene and increased risk of type 2 diabetes mellitus (T2DM) in different populations. Therefore, the present study was designed to investigate the association between Pro12Ala polymorphism of PPAR-γ2 gene and T2DM in an Iranian population. MATERIALS AND METHODS: Two hundred unrelated people, including 100 healthy controls and 100 diabetic patients were recruited diagnosed based on American Diabetes Association criteria. Blood samples were used for isolation of genomic deoxyribonucleic acid (DNA). Having extracted the genomic DNA from human blood leukocytes by means of High Pure polymerase chain reaction (PCR) Template preparation kit, we carried out polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on each blood sample. Then, Genomic DNA was digested by BstU-I restriction enzyme. Thereafter, restriction products were analyzed by means of Polyacrylamide gel electrophoresis and stained by Ethidium Bromide. RESULTS: We found that the frequency of Ala allele in healthy subjects was significantly higher than in diabetic subjects (P = 0003). Moreover, the genotype frequency of Ala/Ala in healthy subjects was significantly higher than in diabetic subjects (P < 0.001). However, the genotype frequency of Ala/Pro in diabetic subjects was significantly higher than in healthy subjects (P < 0.001). CONCLUSION: The present study suggests that polymorphism of PPAR-γ2 gene is associated with T2DM. Furthermore, Ala allele is significantly found in non-diabetic individual’s Iranian population.
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Affiliation(s)
- Azadeh Motavallian
- Department of Pharmacology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Zhang R, Wang J, Yang R, Sun J, Chen R, Luo H, Liu D, Cai D. Effects of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ2 gene on metabolic syndrome risk: a meta-analysis. Gene 2013; 535:79-87. [PMID: 24012868 DOI: 10.1016/j.gene.2013.07.087] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 07/10/2013] [Accepted: 07/23/2013] [Indexed: 12/22/2022]
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.
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Affiliation(s)
- Ruyi Zhang
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Jiao Wang
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Rui Yang
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Jia Sun
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Rongping Chen
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Haizhao Luo
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Duan Liu
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
| | - Dehong Cai
- Department of Endocrinology, Southern Medical University, Zhujiang Hospital, 253# Industry Road, 510282 Guangzhou, Guangdong, China.
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Wang X, Liu J, Ouyang Y, Fang M, Gao H, Liu L. The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population. PLoS One 2013; 8:e71985. [PMID: 23991018 PMCID: PMC3749141 DOI: 10.1371/journal.pone.0071985] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 07/05/2013] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity. METHODS AND FINDINGS A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49-0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42-0.96; P = 0.030). CONCLUSION Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population.
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Affiliation(s)
- Xia Wang
- Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, China
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Liu
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingying Ouyang
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Fang
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Gao
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Luo W, Guo Z, Wu M, Hao C, Hu X, Zhou Z, Zhou Z, Yao X, Zhang L, Liu J. Association of peroxisome proliferator-activated receptor α/δ/γ with obesity, and gene-gene interaction, in the Chinese Han population. J Epidemiol 2013; 23:187-94. [PMID: 23545576 PMCID: PMC3700259 DOI: 10.2188/jea.je20120110] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARs) with obesity and the additional role of gene-gene interaction. METHODS Participants were recruited within the framework of the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort population survey of an urban community in China. In total, 820 subjects (513 nonobese adults, 307 obese adults) were randomly selected, and no individuals were consanguineous. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped and analyzed. RESULTS After covariate adjustment, minor alleles of rs2016520 in PPARδ and rs10865170 in PPARγ were associated with lower BMI (P < 0.01 for all). Generalized multifactor dimensionality reduction analysis showed significant gene-gene interaction among rs2016520, rs9794, and rs10865170 in 3-dimensional models (P = 0.0010); prediction accuracy was 0.6011 and cross-validation consistency was 9/10. It also showed significant gene-gene interaction between rs2016520 and rs10865170 in all 2-dimensional models (P = 0.0010); prediction accuracy was 0.6072 and cross-validation consistency was 9/10. CONCLUSIONS rs2016520 and rs10865170 were associated with lower obesity risk. In addition, interaction was identified among rs2016520, rs9794, and rs10865170 in obesity.
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Affiliation(s)
- Wenshu Luo
- Changzhou Center for Disease Control and Prevention, Changzhou, Jiangsu, China
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Gene-gene interaction between PPARδ and PPARγ is associated with abdominal obesity in a Chinese population. J Genet Genomics 2012; 39:625-31. [PMID: 23273766 DOI: 10.1016/j.jgg.2012.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/31/2012] [Accepted: 08/16/2012] [Indexed: 10/27/2022]
Abstract
The peroxisome proliferator-activated receptors (PPARs) -α, -δ/β and -γ are the ligand-activated transcription factors that function as the master regulators of glucose, fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation, inflammation, and atherosclerosis. The objective of the current study was to examine the main and interactive effect of seven single nucleotide polymorphisms (SNPs) of PPARδ/γ in contribution to abdominal obesity. A total of 820 subjects were randomly selected and no individuals were related. The selected SNPs in PPARδ (rs2016520 and rs9794) and PPARγ (rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped. Mean difference and 95% confident interval were calculated. Interactions were explored by the method of generalized multifactor dimensionality reduction. After adjustment for gender, age, and smoking status, it was found that the carriers of the C allele (TC + CC) of rs2016520 were associated with a decreased risk of abdominal obesity compared to the carriers of the TT genotype (mean difference = -2.63, 95% CI = -3.61--1.64, P < 0.0001). A significant two-locus model (P = 0.0107) involving rs2016520 and rs10865710 and a significant three-locus model (P = 0.0107) involving rs2016520, rs9794, and rs1805192 were observed. Overall, the three-locus model had the highest level of testing accuracy (59.85%) and showed a better cross-validation consistency (9/10) than two-locus model. Therefore, for abdominal obesity defined by waist circumference, we chose the three-locus model as the best interaction model. In conclusion, the C allele in rs2016520 was significantly associated with a lower abdominal obesity. Moreover, an interaction among rs2016520, rs1805192, and rs9794 on incident abdominal obesity could be demonstrated.
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Wang J, Wang C, Tian R, Huang YZ, Lai XS, Lan XY, Wang JQ, Chen H. Sequence variants in the bovine PRDM16 gene associated with body weight in Chinese cattle breeds. GENETICS AND MOLECULAR RESEARCH 2012; 11:746-55. [PMID: 22576833 DOI: 10.4238/2012.march.22.5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
As a zinc-finger protein, PR domain containing 16 (PRDM16) controls brown fat determination by stimulating brown fat cell production while suppressing the expression of genes for production of white fat cells; mutations in this domain are associated with myelodysplastic syndrome and leukemogenesis. In our study, polymorphisms in exons 2, 3, 4, 5, 7, 8, and 9 of the PRDM16 gene were detected by PCR-SSCP, DNA sequencing and CRS-PCR-RFLP methods in 1031 cattle of the Chinese breeds: Jiaxian, Nanyang, Qinchuan, and Chinese Holstein. Three mutations (NC_007314.3: g.577 G>T, 614 T>C, 212237 T>C) were detected. Animals with the homozygote genotype had lower body weight and average daily gain than those with the other genotypes. PRDM16 gene-specific SNPs may be useful markers for growth traits for marker-assisted selection programs.
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Affiliation(s)
- J Wang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Prakash J, Srivastava N, Awasthi S, Agarwal C, Natu S, Rajpal N, Mittal B. Association of PPAR-γ gene polymorphisms with obesity and obesity-associated phenotypes in North Indian population. Am J Hum Biol 2012; 24:454-9. [PMID: 22410809 DOI: 10.1002/ajhb.22245] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 12/24/2011] [Accepted: 01/02/2011] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVES The worldwide increasing prevalence of obesity is considered as a major health problem. Peroxisome proliferator-activated receptor gamma (PPAR-γ) controls adipocyte differentiation and regulates a number of genes associated with energy homeostasis. In this study, we investigated the association of PPAR-γ gene Pro12Ala (rs1801282) and C1431T (rs3856806) polymorphisms with morbid obesity and related phenotypes, in north Indian population. METHODS A total of 6,42 subjects, 309, obese and 333 nonobese individuals were included in this case-control study. Insulin, adiponectin, glucose, and lipid levels were estimated using standard protocols. All subjects were genotyped by PCR restriction fragment length polymorphism (PCR-RFLP) method. RESULTS The ProAla+AlaAla genotypes of PPAR-γ Pro12Ala were significantly associated with higher risk of obesity while C1431T polymorphism did not show any significant association. None of the haplotypes showed association with morbid obesity. However, a strong association of variant genotypes was observed with higher levels of insulin, HOMA-IR, and lower serum adiponectin concentrations. CONCLUSION PPAR-γ gene polymorphisms influence obesity and obesity phenotype in a complex manner, probably involving insulin resistance in north Indian population.
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Affiliation(s)
- Jai Prakash
- Chatrapati Shahuji Maharaj Medical University, Lucknow, U.P., India
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Ackert-Bicknell CL. HDL cholesterol and bone mineral density: is there a genetic link? Bone 2012; 50:525-33. [PMID: 21810493 PMCID: PMC3236254 DOI: 10.1016/j.bone.2011.07.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 06/27/2011] [Accepted: 07/04/2011] [Indexed: 12/16/2022]
Abstract
Overwhelming evidence has linked cardiovascular disease and osteoporosis, but the shared root cause of these two diseases of the elderly remains unknown. Low levels of high density lipoprotein cholesterol (HDL) and bone mineral density (BMD) are risk factors for cardiovascular disease and osteoporosis respectively. A number of correlation studies have attempted to determine if there is a relationship between serum HDL and BMD but these studies are confounded by a number of variables including age, diet, genetic background, gender and hormonal status. Collectively, these data suggest that there is a relationship between these two phenotypes, but that the nature of this relationship is context specific. Studies in mice plainly demonstrate that genetic loci for BMD and HDL co-map and transgenic mouse models have been used to show that a single gene can affect both serum HDL and BMD. Work completed to date has demonstrated that HDL can interact directly with both osteoblasts and osteoclasts, but no direct evidence links bone back to the regulation of HDL levels. Understanding the genetic relationship between BMD and HDL has huge implications for understanding the clinical relationship between CVD and osteoporosis and for the development of safe treatment options for both diseases.
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Abstract
Several candidate gene studies on the metabolic syndrome (MetS) have been conducted. However, for most single nucleotide polymorphisms (SNPs) no systematic review on their association with MetS exists. A systematic electronic literature search was conducted until the 2nd of June 2010, using HuGE Navigator. English language articles were selected. Only genes of which at least one SNP-MetS association was studied in an accumulative total population ≥ 4000 subjects were included. Meta-analyses were conducted on SNPs with three or more studies available in a generally healthy population. In total 88 studies on 25 genes were reviewed. Additionally, for nine SNPs in seven genes (GNB3, PPARG, TCF7L2, APOA5, APOC3, APOE, CETP) a meta-analysis was conducted. The minor allele of rs9939609 (FTO), rs7903146 (TCF7L2), C56G (APOA5), T1131C (APOA5), C482T (APOC3), C455T (APOC3) and 174G>C (IL6) were more prevalent in subjects with MetS, whereas the minor allele of Taq-1B (CETP) was less prevalent in subjects with the MetS. After having systematically reviewed the most studied SNP-MetS associations, we found evidence for an association with the MetS for eight SNPs, mostly located in genes involved in lipid metabolism.
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Affiliation(s)
- C M Povel
- National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
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Association of serum lipid/lipoprotein with Pro12Ala polymorphism in PPAR-γ2 among Chinese nonagenarians/centenarians. Arch Med Res 2011; 42:613-9. [PMID: 22001700 DOI: 10.1016/j.arcmed.2011.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 09/08/2011] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS In previous studies, the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) was shown to be associated with both lipid metabolism and longevity. We examined whether the polymorphism continued to be associated with abnormal levels of serum lipid/lipoprotein among elderly subjects (≥90 years). METHODS The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Abnormal levels of serum lipid/lipoprotein were defined according to the criteria provided by the Chinese Medical Association (2004). Abnormal criteria were triglyceride (TG) >5.18 mmol/l, total cholesterol (TC) >1.7 mmol/l, low-density lipoprotein cholesterol (LDL-C) >3.37 mmol/l and high-density lipoprotein cholesterol (HDL-C) <1.04 mmol/l). RESULTS The sample included 673 unrelated Chinese individuals aged 90-108 years (mean age: 93.54 ± 3.54 years) and 67.3% females. Genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 8.9% Pro12Ala, 91.1% Pro12Pro. Neither differences in the levels of serum lipid/lipoprotein nor the prevalence of their abnormal levels was significant between subjects who were or were not 12Ala carriers. Unadjusted and adjusted multiple logistic regressions showed that the odds ratios (OR) for abnormal levels of serum lipid/lipoprotein were not associated with the Pro12Ala polymorphism in PPAR-γ2. CONCLUSIONS Levels of serum lipid/lipoprotein were not associated with the Pro12Ala polymorphism in PPAR-γ2 among Chinese nonagenarians and centenarians, which was different from the general population.
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Kang SH, Lee JI, Chang AK, Joo YH, Kim CY, Kim SY. Genetic Polymorphisms in the HTR2C and Peroxisome Proliferator-Activated Receptors Are Not Associated with Metabolic Syndrome in Patients with Schizophrenia Taking Clozapine. Psychiatry Investig 2011; 8:262-8. [PMID: 21994515 PMCID: PMC3182393 DOI: 10.4306/pi.2011.8.3.262] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Revised: 12/28/2010] [Accepted: 01/12/2011] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine. METHODS One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III. RESULTS The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype. CONCLUSION We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T) and MetS in patients with schizophrenia taking clozapine.
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Affiliation(s)
- Shi Hyun Kang
- Department of Psychiatry, Seoul National Hospital, Seoul, Korea
| | - Jong Il Lee
- Department of Psychiatry, Seoul National Hospital, Seoul, Korea
| | - An Kee Chang
- Department of Psychiatry, Seoul National Hospital, Seoul, Korea
| | - Yeon Ho Joo
- Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Yoon Kim
- Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seong Yoon Kim
- Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Ackert-Bicknell C, Rosen C. The Genetics of PPARG and the Skeleton. PPAR Res 2011; 2006:93258. [PMID: 17347532 PMCID: PMC1679963 DOI: 10.1155/ppar/2006/93258] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Revised: 06/27/2006] [Accepted: 07/05/2006] [Indexed: 11/17/2022] Open
Abstract
Osteoporosis is a complex metabolic bone disorder. Recently it has been
appreciated that the “obesity in bone” phenomenon occurs at the expense of bone formation, and that is a key component of the pathology of this disease. Mouse models
with altered bone expression levels of peroxisome proliferator-activated receptor gamma
(PPARG) impact bone formation, but genetic studies connecting PPARG polymorphisms to skeletal phenotypes in humans have proven to be less than satisfactory. One missense polymorphism in exon one has been linked to low bone mineral density (BMD), but the most studied polymorphism, Pro12Ala, has not yet been examined in the context of skeletal phenotype. The studies to date are a promising start in leading to our understanding of the genetic contribution of PPARG to the phenotypes of BMD and fracture risk.
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Affiliation(s)
| | - Clifford Rosen
- The Jackson Laboratory, Bar Harbor ME 04609, USA
- St. Joseph's Hospital, The Maine Center for Osteoporosis Research and Education, Bangor ME 04401, USA
- *Clifford Rosen:
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Huang X, Zhao J, Zhao T. Effects of peroxisome proliferator activated receptor-gamma 2 gene Pro12Ala polymorphism on fasting blood lipids: A meta-analysis. Atherosclerosis 2011; 215:136-44. [DOI: 10.1016/j.atherosclerosis.2010.11.043] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/28/2010] [Accepted: 11/30/2010] [Indexed: 11/27/2022]
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Chen CH, Lu ML, Kuo PH, Chen PY, Chiu CC, Kao CF, Huang MC. Gender differences in the effects of peroxisome proliferator-activated receptor γ2 gene polymorphisms on metabolic adversity in patients with schizophrenia or schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:239-45. [PMID: 21095215 DOI: 10.1016/j.pnpbp.2010.11.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Revised: 10/27/2010] [Accepted: 11/08/2010] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Metabolic syndrome (MS) is a major health problem in schizophrenic patients. Peroxisome proliferator-activated receptor γ2 (PPARγ2) is one of the candidate genes responsible for the liability to metabolic problems. In this study, we investigated the effect of the PPARγ2 gene Pro12Ala and C161T polymorphisms on metabolic adversities in patients with schizophrenia or schizoaffective disorder. METHODS Metabolic profiles and PPARγ2 gene polymorphisms were determined in 600 patients (309 men and 291 women) with a clinical diagnosis of schizophrenia or schizoaffective disorder. Metabolic indices and components of MS were compared between patients with different Pro12Ala or C161T genotypes. RESULTS In the whole population, the allele frequency of 12Ala and 161T was 4.4% and 24.7% respectively. Both polymorphisms had no significant effect on obesity or metabolic-related traits. However, following gender stratification of the data, we found female 12Ala allele carriers were at greater risk of developing abdominal obesity (OR = 4.0, 95% CI = 1.1-14.2, p = 0.04) and hypertension (OR=2.9, 95% CI = 1.2-7.4, p = 0.02) than female 12Ala allele non-carriers. Male 161T allele carriers had lower insulin levels (p = 0.02) and lower high-density lipoprotein cholesterol (HDL-C) (p = 0.05) levels than male 161T allele non-carriers. Moreover, female 161T allele carriers had higher body weight (p = 0.04), waist circumference (p = 0.05), and systolic blood pressure (p = 0.01), and were at greater risk of developing hypertension (OR = 2.0, 95% CI = 1.1-3.5, p = 0.02). Haplotype analyses showed that PPARγ2 gene polymorphisms were significantly associated with HDL-C level in men and blood pressure in women. CONCLUSIONS We did not find an association of PPARγ2 gene polymorphisms with MS or obesity in our schizophrenia sample. But further analyses by gender stratification revealed gender-specific differences in the effect of different PPARγ2 genotypes on certain metabolic adversities in these patients.
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Affiliation(s)
- Chun-Hsin Chen
- Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
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Costa V, Gallo MA, Letizia F, Aprile M, Casamassimi A, Ciccodicola A. PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues. PPAR Res 2010; 2010:409168. [PMID: 20871817 PMCID: PMC2943117 DOI: 10.1155/2010/409168] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 07/08/2010] [Indexed: 01/01/2023] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most extensively studied ligand-inducible transcription factors (TFs), able to modulate its transcriptional activity through conformational changes. It is of particular interest because of its pleiotropic functions: it plays a crucial role in the expression of key genes involved in adipogenesis, lipid and glucid metabolism, atherosclerosis, inflammation, and cancer. Its protein isoforms, the wide number of PPARγ target genes, ligands, and coregulators contribute to determine the complexity of its function. In addition, the presence of genetic variants is likely to affect expression levels of target genes although the impact of PPARG gene variations on the expression of target genes is not fully understood. The introduction of massively parallel sequencing platforms-in the Next Generation Sequencing (NGS) era-has revolutionized the way of investigating the genetic causes of inherited diseases. In this context, DNA-Seq for identifying-within both coding and regulatory regions of PPARG gene-novel nucleotide variations and haplotypes associated to human diseases, ChIP-Seq for defining a PPARγ binding map, and RNA-Seq for unraveling the wide and intricate gene pathways regulated by PPARG, represent incredible steps toward the understanding of PPARγ in health and disease.
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Affiliation(s)
- Valerio Costa
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” (IGB), CNR, 80131 Naples, Italy
| | | | - Francesca Letizia
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” (IGB), CNR, 80131 Naples, Italy
| | - Marianna Aprile
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” (IGB), CNR, 80131 Naples, Italy
| | - Amelia Casamassimi
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” (IGB), CNR, 80131 Naples, Italy
- Department of General Pathology, 1st School of Medicine, Second University of Naples, 80138 Naples, Italy
| | - Alfredo Ciccodicola
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” (IGB), CNR, 80131 Naples, Italy
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Juang JMJ, de las Fuentes L, Waggoner AD, Gu CC, Dávila-Román VG. Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function. BMC MEDICAL GENETICS 2010; 11:65. [PMID: 20426853 PMCID: PMC2874543 DOI: 10.1186/1471-2350-11-65] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2009] [Accepted: 04/28/2010] [Indexed: 01/04/2023]
Abstract
BACKGROUND Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain. METHODS Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism. RESULTS By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01). CONCLUSIONS Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.
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Affiliation(s)
- Jyh-Ming Jimmy Juang
- Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Lisa de las Fuentes
- Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Alan D Waggoner
- Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - C Charles Gu
- Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Víctor G Dávila-Román
- Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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The Ala allele in the PPAR-gamma2 gene is associated with reduced risk of type 2 diabetes mellitus in Caucasians and improved insulin sensitivity in overweight subjects. Br J Nutr 2010; 104:488-97. [PMID: 20420754 DOI: 10.1017/s0007114510000851] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The purpose of the present study was to identify the association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with diabetes, insulinaemia and insulin resistance. A meta-analysis study was carried out based on studies conducted in the last 10 years, using the databases PubMed, ISI Web of Knowledge, High Wire Press and Scielo, and the reference lists of the obtained articles. We included original studies that showed the relationship between the Pro12Ala polymorphism in the PPAR-gamma2 gene and type 2 diabetes mellitus (T2DM), insulinaemia and insulin resistance. Statistical analyses were conducted using the program RevMAn 5.0. The Mantel-Haenszel test was used to estimate the OR and the 95 % CI of the dichotomous variable, while the standardised effect size was used to estimate the average standardised mean difference and 95 % CI of continuous variables. The studies were subgrouped by ethnicity and overweight status. Forty-one studies were analysed, including a global sample of 30 612 subjects. We found a significant association of the Ala allele with the lowest risk of T2DM in Caucasians (OR 0.80; 95 % CI 0.65, 0.98), lower serum insulin (standardised effect size: - 0.05; 95 % CI - 0.09, - 0.00; P = 0.04), and greater sensitivity to insulin in overweight individuals (homeostasis model assessment of insulin resistance standardised effect size: - 0.07; 95 % CI - 0.13, - 0.01; P = 0.02). Considering that the Pro12Ala polymorphism in the PPAR-gamma2 gene is one of the factors related to insulin sensitivity, the present study demonstrated a significant effect of the Ala allele on lower development of T2DM in Caucasians and greater sensitivity to insulin in overweight subjects.
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Wang J, Li ZJ, Lan XY, Hua LS, Huai YT, Huang YZ, Ma L, Zhao M, Jing YJ, Chen H, Wang JQ. Two novel SNPs in the coding region of the bovine PRDM16 gene and its associations with growth traits. Mol Biol Rep 2010; 37:571-7. [PMID: 19760096 DOI: 10.1007/s11033-009-9816-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 09/03/2009] [Indexed: 11/25/2022]
Abstract
As a zinc-finger protein, PR domain containing 16 (PRDM16) controls brown fat determination by stimulating brown fat-selective genes expression while suppressing the expression of genes selective for white fat cells, whose mutations were associated with myelodysplastic syndrome (MDS) and leukemogenesis in human and murine model of leukemia. To date, no polymorphisms of PRDM16 gene in bovine had been reported. Herein, PCR-SSCP and DNA sequencing methods were employed to screen the genetic variation within PRDM16 gene in 1031 Chinese indigenous bovine. The results revealed two novel silent mutations: XM_001788152: m.1641T>C (547aa), 1881G>A (627aa). Hence, we described the PvuII and HaeIII forced PCR-RFLP methods for detecting these mutations, respectively. In the forced PCR-RFLP analysis with PvuII, the frequencies of bovine PRDM16-C allele varied from 0.044 to 0.506 in four Chinese native breeds. In the forced PCR-RFLP analysis with HaeIII, the frequencies of bovine PRDM16-G allele were 0.474, 0.494, 0.576 and 0.906 for Jiaxian (JX), Nanyang (NY), Qinchuan (QC) and Chinese Holstein (CH) population. Significant statistical differences between genotypic frequencies implied that both of the polymorphic loci were significantly associated with cattle breeds by the chi square test (chi2 = 190.058, P < 0.001 and chi2 = 118.239, P < 0.001 for PvuII; chi2 = 209.842, P < 0.001 and chi2 = 108.711, P < 0.001 for HaeIII). The associations of the PvuII and HaeIII forced PCR-RFLPs of bovine PRDM16 loci with growth traits were analyzed in Nanyang breed. The two SNPs were associated with body weight and average daily gain in Nanyang aged 12 months, individuals with genotype TT and AA showed significantly better body weight (P < 0.05) and average daily gain (P < 0.01) at 12 months, respectively.
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Affiliation(s)
- J Wang
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Molecular Biology for Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, China.
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Chistiakov DA, Potapov VA, Khodirev DS, Shamkhalova MS, Shestakova MV, Nosikov VV. The PPARgamma Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diab Vasc Dis Res 2010; 7:56-62. [PMID: 20368233 DOI: 10.1177/1479164109347689] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The second isoform of the PPARgamma2 is specific for adipose tissue. In adipocytes, this isoform is involved in the regulation of adipogenesis and lipid storage, insulin and glucose metabolism. Pro12Ala, a missense mutation in exon 2 of PPARG, reduces transcriptional activity of PPARgamma2 and is shown to be associated with increased insulin sensitivity and protection from T2D. Previously, this polymorphism has never been assessed in a Russian population for its relationship to T2D, insulin resistance, and diabetes-related metabolic traits. In this study, we tested 588 Russian T2D patients and 597 normoglycaemic controls. Carriers of the Pro12 allele and subjects homozygous for Pro/Pro had significantly increased risk of developing T2D (OR 1.43 and 2.04, respectively). In Pro/Pro homozygotes, adjustment for potential confounding risk factors resulted in reducing the OR value from 2.04 to 1.69, but the association remained significant (p=0.046).The Pro/Pro genotype also showed association with increased levels of fasting insulin (p=0.019) in non-diabetic controls and elevated serum triglycerides (p=0.019) in T2D patients. Compared with other genotypes, non-diabetic and diabetic subjects homozygous for Pro/Pro had a significantly higher HOMA-IR score and reduced ISI value. This observation strongly supports the implication of the PPARG Pro12Ala in insulin resistance and T2D in a Russian population.
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Oh SH, Park SM, Park JS, Jang AS, Lee YM, Uh ST, Kim YH, Choi IS, Kim MK, Park BL, Shin HD, Park CS. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2009; 1:30-5. [PMID: 20224667 PMCID: PMC2831569 DOI: 10.4168/aair.2009.1.1.30] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 08/31/2009] [Indexed: 12/30/2022]
Abstract
Purpose Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA. Methods Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His). Results Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04). Conclusions The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma.
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Affiliation(s)
- Sun-Hee Oh
- Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University, Bucheon Hospital, Bucheon, Korea
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Tellechea ML, Aranguren F, Pérez MS, Cerrone GE, Frechtel GD, Taverna MJ. Pro12Ala polymorphism of the peroxisome proliferatoractivated receptor-gamma gene is associated with metabolic syndrome and surrogate measures of insulin resistance in healthy men: interaction with smoking status. Circ J 2009; 73:2118-24. [PMID: 19745552 DOI: 10.1253/circj.cj-09-0320] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND The Pro12Ala polymorphism (rs1801282), a nonsynonymous substitution of peroxisome proliferator-activated receptor-gamma (PPARG), has been robustly associated with type 2 diabetes. However, its role in metabolic syndrome (MetS) remains poorly understood. The associations among rs1801282, MetS and surrogate measures of insulin resistance (IR) were investigated in the present study. METHODS AND RESULTS A cross-sectional population-based survey of 572 unrelated healthy male Argentinian blood donors with normal findings on medical examination and not taking any medication was conducted. MetS was assessed using the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) criteria, and the HOMA-IR, and QUICKI were calculated. Genotyping of rs1801282 was performed using RFLP-PCR. The prevalence of MetS was 26.2%. The Pro/Ala genotype (and the Ala12 allele) was associated with a high risk for MetS (odds ratio (OR) 1.67 [95% confidence interval (CI) 1.03-2.72], P=0.0394). This was highlighted among nonsmokers (OR 2.20 [95%CI 1.25-3.88], P=0.0059). ANCOVA confirmed an interaction between smoking status and this association (P=0.031). Ala12 carriers had a higher waist circumference than noncarriers (P=0.0065). Among nonsmokers, surrogates of IR, such as HOMA-IR, were significantly higher in Ala12 carriers than in noncarriers (P<0.05). CONCLUSIONS Healthy men, in particular nonsmokers, carrying the Ala12 allele of PPARG rs1801282 polymorphism, have a high risk for MetS and IR.
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Affiliation(s)
- Mariana L Tellechea
- Laboratory of Molecular Biology, Department of Genetics and Molecular Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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Single-nucleotide polymorphisms in peroxisome proliferator-activated receptor γ and their association with plasma levels of resistin and the metabolic syndrome in a South Indian population. J Biosci 2009; 34:405-14. [DOI: 10.1007/s12038-009-0047-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Yang LL, Hua Q, Liu RK, Yang Z. Association between two common polymorphisms of PPARgamma gene and metabolic syndrome families in a Chinese population. Arch Med Res 2009; 40:89-96. [PMID: 19237017 DOI: 10.1016/j.arcmed.2008.11.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2008] [Accepted: 11/03/2008] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND AIMS We investigated the association between the two common polymorphisms, C1431T and Pro12Ala of PPARgamma gene, and metabolic syndrome (MS) in a Chinese population. METHODS We included 423 subjects with MS and families without MS. Subjects were divided into three groups: MS probands and first- and second-degree relatives of probands, spouses and controls. Each group was then divided into two subgroups according to genotype (Pro/Pro and Pro/Ala for Pro12Ala, CC and CT + TT for 1431C/T). Anthropometric indices, fasting plasma glucose, lipid profile, Sv1 + Rv5 of electrocardiogram and single nucleotide polymorphisms were detected. RESULTS Frequencies of C1431T genotypes, but not Pro12Ala, were different among the three groups. MS patients with Pro/Ala genotype had higher fasting blood sugar (FBS) levels and Sv1 + Rv5. Controls with Ala allele had lower total cholesterol levels. In relatives, Ala carriers had higher high-density lipoprotein cholesterol (HDL-c) levels. BMI of the different groups were not significant. MS patients with T allele had higher FBS and Sv1 + Rv5. In relatives of MS subjects, T-allele carriers had lower blood uric acid, creatinine and higher HDL-c levels and Sv1 + Rv5. CONCLUSIONS C1431T, but not Pro12Ala polymorphisms, are associated with MS in a Chinese population. In MS patients, Ala allele and T allele are both associated with higher fasting blood sugar and higher left ventricular voltage. In controls, Ala carriers have lower total cholesterol. In MS relatives, Ala carriers had higher HDL-c levels and T-allele carriers had lower uric acid, creatinine and higher HDL-c levels and left ventricular voltage.
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Affiliation(s)
- Li Lan Yang
- Department of Cardiology, Xuanwu Hospital of the Capital University of Medical Science, Beijing, China
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Dongxia L, Qi H, Lisong L, Jincheng G. Association of peroxisome proliferator-activated receptorgamma gene Pro12Ala and C161T polymorphisms with metabolic syndrome. Circ J 2008; 72:551-7. [PMID: 18362424 DOI: 10.1253/circj.72.551] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
UNLABELLED BACKGROUND Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved mainly in adipocyte differentiation and has been suggested to play an important role in the pathogenesis of insulin resistance (IR) and atherosclerosis. The frequencies of 2 common polymorphisms of the PPARgamma gene, Pro12Ala single nucleotide polymorphism (SNP) in exon B and C161T SNP in exon 6, were investigated in 792 subjects and the correlations between the different genotypes, IR and metabolic syndrome (MS) were analyzed. METHODS AND RESULTS Anthropometric measurements, fasting glucose, insulin and lipid profiles were measured in 792 people of the Han population in Beijing, China. Homeostatic model assessments and quantitative insulin sensitivity check indices were calculated. MS was diagnosed according to the IDF guidelines (2005) for a Chinese population. Polymerase chain reaction - restriction fragment length polymorphism were performed for DNA genotyping. For the C161T polymorphism, allele frequencies were 0.804 for the C allele and 0.196 for the T allele. For Pro12Ala, allele frequencies were 0.947 for proline and 0.053 for alanine. There was no Ala12Ala homozygote in the population. No differences were seen in the mean values of age, body mass index (BMI), blood pressure or fasting blood glucose level among different genotypes when analyzed as a whole. Subjects with an A or T allele had lower fasting insulin levels, HOMA-IR levels, and a lower level QUICKI trend. Further analysis by age was conducted, and A or T allele carriers in the <60 year group showed a trend of lower triglyceride and a higher high-density lipoprotein-cholesterol level, but this was not statistically significant. When subjects were divided into 4 groups according to the combination of genetic alleles of the 2 polymorphisms, the subjects with Pro12Ala and a T allele simultaneously showed a significantly higher BMI than those without the Ala allele. The presence of a T allele in the C161T polymorphism and Pro12Ala polymorphism seems to affect body weight, which is similar to the results found in previous studies. CONCLUSIONS Both polymorphisms showed a significant association with IR, but failed to show an association with MS components. Those with an A allele of Pro12Ala and a T allele of the C161T polymorphism showed a higher BMI, which requires further investigation.
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Affiliation(s)
- Liu Dongxia
- Department of Cardiology, Xuanwu Hospital, Capital Medical University, Beijing, China
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Montagnana M, Fava C, Nilsson PM, Engström G, Hedblad B, Lippi G, Minuz P, Berglund G, Melander O. The Pro12Ala polymorphism of the PPARG gene is not associated with the metabolic syndrome in an urban population of middle-aged Swedish individuals. Diabet Med 2008; 25:902-8. [PMID: 18959602 DOI: 10.1111/j.1464-5491.2008.02510.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. METHODS MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. RESULTS Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides (P < 0.05). CONCLUSIONS Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco-metabolic disturbances.
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Affiliation(s)
- M Montagnana
- Department of Clinical Sciences, Lund University, University Hospital of Malmö, Malmö, Sweden.
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Abstract
Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.
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Marín-García J, Goldenthal MJ, Moe GW. Metabolic Syndrome, Diabetes and Cardiometabolic Risks in Aging. AGING AND THE HEART 2007:277-305. [DOI: 10.1007/978-0-387-74072-0_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kotani K, Saiga K, Kurozawa Y, Sakane N, Sano Y, Tabata M. The peroxisome proliferator-activated receptor γ2 gene Pro12Ala polymorphism and serum C-reactive protein in general Japanese population. Clin Chim Acta 2007; 383:178-9. [PMID: 17574226 DOI: 10.1016/j.cca.2007.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Revised: 04/25/2007] [Accepted: 05/02/2007] [Indexed: 11/22/2022]
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Wadén J, Thorn LM, Forsblom C, Lakka T, Saraheimo M, Rosengård-Bärlund M, Heikkilä O, Wessman M, Turunen JA, Parkkonen M, Tikkanen H, Groop PH. Leisure-time physical activity is associated with the metabolic syndrome in type 1 diabetes: effect of the PPARgamma Pro12Ala polymorphism: the FinnDiane Study. Diabetes Care 2007; 30:1618-20. [PMID: 17351273 DOI: 10.2337/dc06-2467] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Johan Wadén
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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Heikkinen S, Auwerx J, Argmann CA. PPARgamma in human and mouse physiology. Biochim Biophys Acta Mol Cell Biol Lipids 2007; 1771:999-1013. [PMID: 17475546 PMCID: PMC2020525 DOI: 10.1016/j.bbalip.2007.03.006] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2006] [Revised: 03/14/2007] [Accepted: 03/19/2007] [Indexed: 11/23/2022]
Abstract
The peroxisome proliferator activated receptor gamma (PPARgamma) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARgamma also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARgamma has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARgamma activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARgamma. It is now evident that the full activation of PPARgamma is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARgamma signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARgamma biology.
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Affiliation(s)
- Sami Heikkinen
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France
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Miller M, Rhyne J, Chen H, Beach V, Ericson R, Luthra K, Dwivedi M, Misra A. APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome. Arch Med Res 2007; 38:444-51. [PMID: 17416293 PMCID: PMC1987381 DOI: 10.1016/j.arcmed.2006.10.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2006] [Accepted: 10/02/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. METHODS One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARalpha and PPARgamma. RESULTS Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively (p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. CONCLUSIONS These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS.
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Affiliation(s)
- Michael Miller
- University of Maryland Hospital and Veterans Affairs Medical Center, Baltimore, Maryland, USA.
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Nitz I, Ewert A, Klapper M, Döring F. Analysis of PGC-1α variants Gly482Ser and Thr612Met concerning their PPARγ2-coactivation function. Biochem Biophys Res Commun 2007; 353:481-6. [PMID: 17187763 DOI: 10.1016/j.bbrc.2006.12.042] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2006] [Accepted: 12/07/2006] [Indexed: 11/20/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1alpha gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-gamma 2 (PPARgamma2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1alpha and PPARgamma2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is the first study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1alpha and Pro12Ala polymorphism in PPARgamma2 do not affect the functional integrity of these proteins.
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Affiliation(s)
- Inke Nitz
- Molecular Nutrition, Christian-Albrechts-University of Kiel, Kiel, Germany.
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