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Horwitz A, Birk R. Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity-The Case of BBS Obesity. Nutrients 2023; 15:3445. [PMID: 37571382 PMCID: PMC10421039 DOI: 10.3390/nu15153445] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/16/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Obesity is a metabolic state generated by the expansion of adipose tissue. Adipose tissue expansion depends on the interplay between hyperplasia and hypertrophy, and is mainly regulated by a complex interaction between genetics and excess energy intake. However, the genetic regulation of adipose tissue expansion is yet to be fully understood. Obesity can be divided into common multifactorial/polygenic obesity and monogenic obesity, non-syndromic and syndromic. Several genes related to obesity were found through studies of monogenic non-syndromic obesity models. However, syndromic obesity, characterized by additional features other than obesity, suggesting a more global role of the mutant genes related to the syndrome and, thus, an additional peripheral influence on the development of obesity, were hardly studied to date in this regard. This review summarizes present knowledge regarding the hyperplasia and hypertrophy of adipocytes in common obesity. Additionally, we highlight the scarce research on syndromic obesity as a model for studying adipocyte hyperplasia and hypertrophy, focusing on Bardet-Biedl syndrome (BBS). BBS obesity involves central and peripheral mechanisms, with molecular and mechanistic alternation in adipocyte hyperplasia and hypertrophy. Thus, we argue that using syndromic obesity models, such as BBS, can further advance our knowledge regarding peripheral adipocyte regulation in obesity.
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Affiliation(s)
| | - Ruth Birk
- Department of Nutrition, Faculty of Health Sciences, Ariel University, Ariel 40700, Israel;
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Muntean C, Sasaran MO, Crisan A, Banescu C. Effects of PPARG and PPARGC1A gene polymorphisms on obesity markers. Front Public Health 2022; 10:962852. [PMID: 36466447 PMCID: PMC9709282 DOI: 10.3389/fpubh.2022.962852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022] Open
Abstract
Pediatric obesity presents a multifactorial etiology, which involves genetic traits as well, including single nucleotide polymorphisms. The aim of the study is to investigate the contribution of PPARG gene polymorphisms (namely Pro12Ala rs1801282, His447His rs3856806, and Pro115Gln rs1800571) and PPARGC1A rs8192678 SNP on the anthropometric and metabolic parameters in a population of Romanian children. We conducted a cross-sectional study of 295 Caucasian children, divided according to the body mass index (BMI) z-score into the study (obese and overweight) group of 130 children and the control (normoponderal) group of 165 children. Anthropometric parameters were greater in the obese and overweight population as opposed to controls, with significant differences (p < 0.01) found for the weight (2.77 ± 1.54 SD vs. -0.04 ± 1.15 SD), body mass index (BMI) (2.28 ± 0.97 SD vs. -0.18 ± 1.19 SD), mid-upper arm circumference (MUAC) (4.59 ± 2.28 SD vs. 0.28 ± 3.45 SD), tricipital skin-fold (TSF) (3.31 ± 3.09 SD vs. 0.62 ± 7.28 SD) and waist-to-height ratio (WHtR) (0.61 ± 1.51 SD vs. -0.35 ± 1.35 SD) z-scores. Moreover, triglyceride values were higher in the study group (118.70 ± 71.99 SD vs. 77.09 ± 37.39 SD). No significant difference in the allele and genotype distribution of investigates gene polymorphisms was observed between the studied groups (p > 0.05). PPARG (rs1801282, rs3856806, and rs1800571) were not associated with demographic, anthropometric, and laboratory parameters. However, PPARGC1A rs8192678 CC genotype was associated with TSF z-score (p = 0.03), whereas total and LDL cholesterol levels were significantly higher among TT homozygotes (p < 0.01). Our data suggest that PPARG (rs1801282, rs3856806, and rs1800571) and PPARGC1A (rs8192678) gene polymorphisms were not associated with childhood and adolescence overweight and obesity. The present study identified a significant increase in fasting glucose levels, triglyceride, albumin, and ALT levels in children with excess weight, as well as expected important upward variation of anthropometric parameters (BMI, MUAC, TSF z-scores).
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Affiliation(s)
- Carmen Muntean
- Department of Paediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences, and Technology of Târgu Mureş, Târgu Mureş, Romania
| | - Maria Oana Sasaran
- Department of Paediatrics III, “George Emil Palade” University of Medicine, Pharmacy, Sciences, and Technology of Târgu Mureş, Târgu Mureş, Romania
| | - Adriana Crisan
- Center for Advanced Medical and Pharmaceutical Research, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş, Romania
| | - Claudia Banescu
- Center for Advanced Medical and Pharmaceutical Research, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş, Romania
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Abaj F, Sotoudeh G, Karimi E, Rafiee M, Koohdani F. Interaction between the dietary indices and PPAR-γ Pro12Ala gene variants on cardiovascular risk factors in patients with type 2 diabetes mellitus. Int J Clin Pract 2021; 75:e14307. [PMID: 33930247 DOI: 10.1111/ijcp.14307] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/27/2021] [Indexed: 01/18/2023] Open
Abstract
AIMS We investigated the interaction between peroxisome proliferator-activated receptor gamma (PPAR-γ) Pro12Ala polymorphism and healthy eating index (HEI), Dietary Quality Index-International (DQI-I), and dietary phytochemical index (DPI) on cardiovascular disease (CVD) risk factors in patients with type 2 diabetes mellitus (T2DM). METHODS This cross-sectional study was conducted on 393 diabetic patients. PPAR-γ Pro12Ala was genotyped by the PCR-RFLP method. Biochemical markers including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), superoxide dismutase (SOD), C-reactive protein (CRP), total antioxidant capacity (TAC), pentraxin-3 (PTX3), isoprostaneF2α (PGF2α). Interleukin 18 (IL18), leptin, and ghrelin were measured by standard protocol. Food-frequency questionnaires (FFQ) were used for dietary indices (DQI-I, DPI, HEI) calculation. RESULTS Homozygous carriers of the rs1801282 C allele showed higher leptin compared G allele carriers (P = .015). The rs1801282-DQI-I interactions were significant on waist circumference (WC) (P = .019). Thus, C-allele carriers in the higher tertile of DQI-I had higher WC compared with GG homozygous. Further, an interaction was observed between PPAR rs1801282 polymorphism and DQI-I on serum IL-18 level (P = .032). Besides, a significant rs1801282-DPI interaction was shown on HDL concentration (P = .041), G allele carriers who were in the highest tertile of DPI, had lower HDL. Moreover, there were significant rs1801282-HEI interactions on serum leptin (P = .021). Individuals with (CC, CG) genotypes in the higher tertile of HEI, had lower leptin concentration. CONCLUSION Higher dietary indices (DQI-I, DPI, HEI) may affect the relationship between PPAR-γ Pro12Ala polymorphism and WC, ghrelin, leptin, HDL, and IL-18 concentration in patients with T2DM.
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Affiliation(s)
- Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Gity Sotoudeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Elmira Karimi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Masoumeh Rafiee
- Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences (IUMS), Isfahan, Iran
| | - Fariba Koohdani
- Department of Cellular, Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Cataldi S, Costa V, Ciccodicola A, Aprile M. PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine. Curr Diab Rep 2021; 21:18. [PMID: 33866450 DOI: 10.1007/s11892-021-01385-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands. RECENT FINDINGS PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms-generating dominant-negative isoforms mainly expressed in human adipose tissue-have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D. The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.
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Affiliation(s)
- Simona Cataldi
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
| | - Alfredo Ciccodicola
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy.
- Department of Science and Technology, University of Naples "Parthenope", 80131, Naples, Italy.
| | - Marianna Aprile
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy
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Sarhangi N, Sharifi F, Hashemian L, Hassani Doabsari M, Heshmatzad K, Rahbaran M, Jamaldini SH, Aghaei Meybodi HR, Hasanzad M. PPARG (Pro12Ala) genetic variant and risk of T2DM: a systematic review and meta-analysis. Sci Rep 2020; 10:12764. [PMID: 32728045 PMCID: PMC7391673 DOI: 10.1038/s41598-020-69363-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a complex disease caused by the interaction between genetic and environmental factors. A growing number of evidence suggests that the peroxisome proliferator-activated receptor gamma (PPARG) gene plays a major role in T2DM development. Meta-analysis of genetic association studies is an efficient tool to gain a better understanding of multifactorial diseases and potentially to provide valuable insights into gene-disease interactions. The present study was focused on assessing the association between Pro12Ala variation in the PPARG and T2DM risk through a comprehensive meta-analysis. We searched PubMed, WoS, Embase, Scopus and ProQuest from 1990 to 2017. The fixed-effect or random-effect model was used to evaluate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) depending on the heterogeneity among studies. The sources of heterogeneity and publication bias among the included studies were assessed using I2 statistics and Egger's tests. A total of 73 studies, involving 62,250 cases and 69,613 controls were included. The results showed that the minor allele (G) of the rs1801282 variant was associated with the decreased risk of T2DM under different genetic models. Moreover, the protective effect of minor allele was detected to be significantly more in some ethnicities including the European (18%), East Asian (20%), and South East Asian (18%). And the reduction of T2DM risk in Ala12 carriers was stronger in individuals from North Europe rather than Central and South Europe. Our findings indicated that the rs1801282 variant may contribute to decrease of T2DM susceptibility in different ancestries.
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Affiliation(s)
- Negar Sarhangi
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, 1411413137, Tehran, Iran
| | - Farshad Sharifi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, 1411413137, Tehran, Iran
| | - Leila Hashemian
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran
| | - Maryam Hassani Doabsari
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran
| | - Katayoun Heshmatzad
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran
| | - Marzieh Rahbaran
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran
| | - Seyed Hamid Jamaldini
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran
| | - Hamid Reza Aghaei Meybodi
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, 1411413137, Tehran, Iran.,Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, 1411413137, Tehran, Iran
| | - Mandana Hasanzad
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, 1411413137, Tehran, Iran. .,Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, 1916893813, Tehran, Iran.
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Khatami F, Mohajeri-Tehrani MR, Tavangar SM. The Importance of Precision Medicine in Type 2 Diabetes Mellitus (T2DM): From Pharmacogenetic and Pharmacoepigenetic Aspects. Endocr Metab Immune Disord Drug Targets 2020; 19:719-731. [PMID: 31122183 DOI: 10.2174/1871530319666190228102212] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/18/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Type 2 Diabetes Mellitus (T2DM) is a worldwide disorder as the most important challenges of health-care systems. Controlling the normal glycaemia greatly profit long-term prognosis and gives explanation for early, effective, constant, and safe intervention. MATERIAL AND METHODS Finding the main genetic and epigenetic profile of T2DM and the exact molecular targets of T2DM medications can shed light on its personalized management. The comprehensive information of T2DM was earned through the genome-wide association study (GWAS) studies. In the current review, we represent the most important candidate genes of T2DM like CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1, and HNF homeoboxes. Different genetic variations of a candidate gene can predict the efficacy of T2DM personalized strategy medication. RESULTS SLCs and AMPK variations are considered for metformin, CYP2C9, KATP channel, CDKAL1, CDKN2A/2B and KCNQ1 for sulphonylureas, OATP1B, and KCNQ1 for repaglinide and the last but not the least ADIPOQ, PPAR-γ, SLC, CYP2C8, and SLCO1B1 for thiazolidinediones response prediction. CONCLUSION Taken everything into consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad R Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed M Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Zahri MK, Emilia A, Rawi RIM, Taib WRW, Sani AI, Baig AA. Contribution of the Pro12Ala polymorphism of peroxisome proliferator-activated receptor Ɣ2 gene in relation to obesity. Meta Gene 2016. [DOI: 10.1016/j.mgene.2016.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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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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Gok O, Karaali ZE, Acar L, Kilic U, Ergen A. ABCG5 and ABCG8 gene polymorphisms in type 2 diabetes mellitus in the Turkish population. Can J Diabetes 2015; 39:405-10. [PMID: 26088706 DOI: 10.1016/j.jcjd.2015.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 03/23/2015] [Accepted: 04/09/2015] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The aim of the present study was to investigate the relationship between ABCG5 and ABCG8 gene polymorphisms and plasma lipid concentrations in Turkish patients with type 2 diabetes mellitus. METHODS Included in this study were 80 patients with type 2 diabetes and 73 healthy controls. Two selected single nucleotide polymorphisms in ABC transporter genes, ABCG5 (rs6720173) and ABCG8 (rs4148211), were genotyped by using the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS The rate of having the ABCG8 AA genotype (p=0.001) was significantly higher in the patients than in the control subjects. Correspondingly, the rates of having the AG genotype (p=0.001) and the G allele (p=0.001) were significantly lower in the patients than in controls. Upon comparing the groups regarding ABCG5, the frequencies of occurrence of the GG genotype (p=0.031) and G allele (p=0.003) were considerably higher in patients than in control subjects. In the patients, the rates of having the CC genotype (p=0.003) and the C allele (p=0.031) were also significantly lower than those in control subjects. There was no significant difference between G5 and G8 polymorphism and lipid levels in the study groups. The ABCG8 AA genotype carriers had higher triglyceride (p=0.045) and very low-density-cholesterol (p=0.045) levels than the ABCG8 GG genotype carriers in all study populations. CONCLUSIONS These results indicate that the AA genotype for ABCG8 and the GG genotype and G allele for ABCG5 are risk factors for diabetes. This study reveals the first data concerning the ABCG5 and ABCG8 gene polymorphisms in Turkish patients with diabetes.
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Affiliation(s)
- Ozlem Gok
- Department of Molecular Medicine, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey; Department of Medical Biology and Regenerative and Restorative Medicine Research Center (REMER), Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Zeynep Ermis Karaali
- Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey
| | - Leyla Acar
- Department of Molecular Medicine, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Ulkan Kilic
- Department of Medical Biology and Regenerative and Restorative Medicine Research Center (REMER), Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Arzu Ergen
- Department of Molecular Medicine, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.
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Hsiao TJ, Lin E. The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma (PPARG) gene in relation to obesity and metabolic phenotypes in a Taiwanese population. Endocrine 2015; 48:786-93. [PMID: 25182148 DOI: 10.1007/s12020-014-0407-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 08/25/2014] [Indexed: 01/17/2023]
Abstract
Obesity is considered as an important public health problem in the world. Although the association of a common single nucleotide polymorphism (SNP), rs1801282 (Pro12Ala), in the peroxisome proliferator-activated receptor gamma (PPARG) gene with obesity has been reported in various populations, these data are not conclusive. This study aimed to reassess whether the PPARG rs1801282 SNP is linked with obesity and obesity-related metabolic traits in a Taiwanese population. A total of 674 Taiwanese subjects with general health examinations were genotyped. The rs1801282 genotype was determined by the Taqman SNP genotyping assay. Obesity-related metabolic traits such as triglyceride, waist circumference, systolic and diastolic blood pressure, total cholesterol, and fasting glucose were measured. The PPARG rs1801282 SNP did not exhibit any significant association with obesity among the complete sample population. However, sex-stratified analyses revealed an effect on overweight in female participants where the carriers of the combined CG and GG genotypes had a higher risk to overweight than those with the CC homozygotes (OR=4.05; 95% CI=1.28-12.83; P=0.017). Compared to the carriers of CC homozygotes, BMI was significantly higher for the carriers of the combined CG and GG genotypes in the female subjects (24.4±3.7 vs. 23.5±3.8 kg/m2; P=0.033). In addition, the carriers of the CC homozygotes had a higher total cholesterol level than those with the combined CG and GG genotypes in the female subjects (197.0±37.3 vs. 180.7±33.7 mg/dl; P=0.026). Our study indicates that PPARG rs1801282 may significantly predict overweight, BMI, and total cholesterol in female but not male Taiwanese subjects.
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Affiliation(s)
- Tun-Jen Hsiao
- College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
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Black MH, Wu J, Takayanagi M, Wang N, Taylor KD, Haritunians T, Trigo E, Lawrence JM, Watanabe RM, Buchanan TA, Xiang AH. Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes. J Clin Endocrinol Metab 2015; 100:1187-95. [PMID: 25584717 PMCID: PMC4333029 DOI: 10.1210/jc.2014-3246] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Peroxisome proliferator-activated receptor gamma (PPARG) is a susceptibility locus for type 2 diabetes mellitus (T2DM). Although cross-sectional associations have been reported, primarily for Pro12Ala, few longitudinal studies in nondiabetic populations have been conducted. OBJECTIVE This study aimed to examine whether and to what extent variation in PPARG is associated with longitudinal changes in anthropometric and metabolic traits in Mexican Americans at risk for T2DM. SETTING AND DESIGN Subjects were participants of BetaGene, a family-based study of obesity, insulin resistance, and β-cell function, who completed a baseline and follow-up study visit (n = 378; mean followup, 4.6 ± 1.5 y). Phenotypes included body fat assessed by dual-energy x-ray absorptiometry; insulin sensitivity (SI), acute insulin response, and β-cell function (disposition index; DI) were estimated from iv glucose tolerance tests with Minimal Model analysis. Eighteen tag single nucleotide polymorphisms (SNPs) capturing variation in a 156-kb region surrounding PPARG were tested for association with changes in longitudinal traits. P-values were Bonferroni-corrected for multiple testing. RESULTS Six SNPs (rs2972164, rs11128598, rs17793951, rs1151996, rs1175541, rs3856806) were significantly associated with rate of change in SI after adjustment for age, sex, and body fat percentage, but not with changes in adiposity. rs17793951 also had a significant effect on change in DI over time. Association between rs1175541 and change in SI varied by changes in adiposity such that only carriers of the minor allele who reduced body fat over followup improved SI. rs1306470 (captured Pro12Ala, r(2) = 0.9) was not associated with rates of change in any traits and its effects were not modified by changes in adiposity. CONCLUSIONS Variation in PPARG, but not Pro12Ala, contributes to declining SI and concomitant deterioration in β-cell function in Mexican Americans at risk for T2DM.
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Affiliation(s)
- Mary Helen Black
- Department of Research & Evaluation (M.H.B., J.W., M.T., J.M.L., A.H.X.), Kaiser Permanente Southern California, Pasadena, California; Department of Preventive Medicine (N.W., R.M.W., T.A.B.), Keck School of Medicine of University of Southern California (USC), Los Angeles, California; Medical Genetics Institute (K.D.T., T.H.), Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine (E.T.), Keck School of Medicine of USC, Los Angeles, California; USC Diabetes and Obesity Research Institute (R.M.W., T.A.B.), Los Angeles, California; Department of Physiology & Biophysics (R.M.W., T.A.B.), Keck School of Medicine of USC, Los Angeles, California
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Wang R, Dai L, Chen J. Identification of a proliferator-activated receptor-γ antagonist for the treatment of type 2 diabetes mellitus. Exp Ther Med 2015; 9:446-450. [PMID: 25574213 PMCID: PMC4280942 DOI: 10.3892/etm.2014.2096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 09/25/2014] [Indexed: 01/04/2023] Open
Abstract
In the present study, a novel antagonist of the peroxisome proliferator-activated receptor-γ (PPARγ) was screened and identified, and a cell-based evaluation of the biological activity of this PPARγ antagonist was conducted. The aim of the study was to produce results that may provide a foundation for the development of a novel compound in the treatment of type 2 diabetes mellitus. Since obesity is the main cause of insulin resistance and type 2 diabetes, identifying a new reagent that is able to inhibit adipocyte differentiation and lipid accumulation is a feasible method of developing novel anti-diabetes drugs. The PPARγ antagonist was screened using a mammalian one-hybrid system and transcriptional activation. The effects of the compound on adipocyte differentiation were investigated by staining the preadipocytes with Oil Red O. In addition, the effects of the compound on the expression levels of genes associated with lipid metabolism were detected using quantitative polymerase chain reaction on differentiated mature 3T3-L1 adipocytes. As a PPARγ antagonist, N-((1H-benzo[d]imidazol-2-yl)methyl) aniline (Compound Q) was shown to depress the transcriptional activity and coactivator recruitment of PPARγ, as well as preadipocyte differentiation, in a concentration-dependent manner. The compound was also shown to decrease the expression levels of genes associated with PPARγ-regulated lipid metabolism. In conclusion, the compound screening platform was demonstrated to be valid, and the present study identified a novel PPARγ antagonist that was shown to effectively reduce the rate of adipocyte differentiation and the expression of genes associated with lipid metabolism.
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Affiliation(s)
- Ren Wang
- Department of Ultrasonography, Shanghai Sixth People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai 200233, P.R. China
| | - Lihua Dai
- Department of Emergency, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Jinjin Chen
- Department of Child Health Care, Shanghai Children's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200040, P.R. China
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Association between PPAR-γ2 Pro12Ala polymorphism and obesity: a meta-analysis. Mol Biol Rep 2014; 42:1029-38. [PMID: 25502405 DOI: 10.1007/s11033-014-3838-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 11/11/2014] [Indexed: 10/24/2022]
Abstract
The peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene has been reported in the pathogeny of obesity. However, the results have been inconsistent. The purpose of this meta-analysis was to acquire a more accurate assessment of the association between PPAR-γ2 Pro12Ala polymorphism and obesity. PubMed, Wan Fang (Chinese) databases, Chinese Biomedical Medical databases, and Chinese National Knowledge Infrastructure were searched to identify eligible studies. Finally, 25 studies (6491 cases and 8242 controls) were enrolled in this meta-analysis. The effect summary odds ratio (OR) with 95 % confidence interval (CI) was applied. Random-effects or fixed-effects model was performed based on the heterogeneity. STATA 12.0 was applied for this meta-analysis. The combined results showed that PPAR-γ Pro12Ala polymorphism was associated with the obesity risk (Ala vs. Pro: OR = 1.55, 95 % CI 1.34-1.80; Pro/Ala vs. Pro/Pro: OR = 1.54, 95 % CI 1.31-1.82; Ala/Ala + Pro/Ala vs. Pro/Pro: OR = 1.61, 95 % CI 1.36-1.90). Subgroup analysis by ethnicity showed that there were significant associations between PPAR-γ Pro12Ala polymorphism and obesity risk in Caucasians, Asians, and Mixed population. Subgroup analysis by obesity's cutoff points showed that the associations were found among the patients with the cutoff point of BMI ≥24 and BMI ≥30 but not among the patients with the cutoff point of BMI ≥95th percentile. These results suggested that PPAR-γ Pro12Ala polymorphism might be a risk factor for obesity susceptibility.
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Peroxisome proliferator‑activated receptor γ polymorphisms as risk factors for dyslipidemia. Mol Med Rep 2014; 10:2759-63. [PMID: 25216344 DOI: 10.3892/mmr.2014.2553] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 06/26/2014] [Indexed: 11/05/2022] Open
Abstract
Peroxisome proliferator‑activated receptor γ (PPARγ) may play an important role in lipid metabolism directly or by inducing the transcription of target genes. The aim of the present study was to investigate the association between common variants at the PPARγ locus (C1431T and Pro12Ala polymorphisms) and lipid serum levels. The studied population consisted of 820 subjects randomly selected from the Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province cohort population. All subjects were interviewed and blood samples were obtained for laboratory analysis and DNA extraction. The TaqMan single nucleotide polymorphism genotyping assay was used for polymorphism genotyping. Individual polymorphisms and haplotype data were available for analysis. The 12Ala allele was found to be associated with significantly increased levels of triglyceride (TG) (P<0.01), whilst the 1431T allele was found to be associated with significantly increased levels of TG, total cholesterol (TC) and non‑high‑density lipoprotein (non‑HDL) (P<0.01). When P‑C, the most common haplotype, was used as the reference group, the P‑T, A‑C and A‑T haplotypes were found to be associated with significantly increased levels of TG (P<0.01). In addition, the A‑T haplotype was shown to be associated with significantly increased levels of TC and non‑HDL (P<0.01). In conclusion these results suggest that PPARγ gene variability may increase the risk of dyslipidemia.
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PPAR α and PPAR γ polymorphisms as risk factors for dyslipidemia in a Chinese Han population. Lipids Health Dis 2014; 13:23. [PMID: 24460649 PMCID: PMC3905651 DOI: 10.1186/1476-511x-13-23] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 01/24/2014] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The PPAR α and PPAR γ are the key messengers responsible for the translation of nutritional stimuli into changes for the expression of genes, particularly genes involved in lipid metabolism. However, the associations between PPAR α/γ polymorphisms and lipid serum levels in the general population were rarely studied, and the conclusions were conflicting. The objective was to investigate the associations of the PPAR α and PPAR γ polymorphisms with dyslipidemia. METHODS 820 subjects were randomly selected from the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort populations. The logistic regression model was used to examine the association between these polymorphisms and dyslipidemia. SNPstats was used to explore the haplotype association analyses. RESULTS In the codominant and log-additive models, rs1800206, rs1805192 and rs3856806 were all associated with dyslipidemia (P < 0.005). When the most common haplotype L-G (established by rs1800206, rs4253778) was treated as the reference group, the V-G haplotype was associated with dyslipidemia (P < 0.001), higher TC and TG levels (P < 0.01). Moreover, when compared to Pro-C haplotype (established by rs1805192, rs3856806), the Pro-T, Ala-C, Ala-T haplotypes were associated with dyslipidemia (p < 0.001). A-T haplotype was associated with higher TC levels, (p < 0.01), and the P-T, A-C, A-T haplotypes were associated with higher TG levels (p < 0.01). CONCLUSIONS PPAR α and PPAR γ polymorphisms and haplotypes may be the genetic risk factors for dyslipidemia.
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The Rate of Decline of Glomerular Filtration Rate May Not Be Associated with Polymorphism of the PPARγ2 Gene in Patients with Type 1 Diabetes and Nephropathy. PPAR Res 2014; 2014:523584. [PMID: 24587794 PMCID: PMC3920619 DOI: 10.1155/2014/523584] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 11/12/2013] [Accepted: 11/13/2013] [Indexed: 01/09/2023] Open
Abstract
The aim of the study was to investigate whether a Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene is associated with the progress of diabetic nephropathy in patients with type 1 diabetes. 197 Caucasian patients with type 1 diabetes and ethnically matched 151 normal healthy controls were genotyped for this polymorphism. Results showed that there were no significant differences in the frequencies of the genotypes and alleles of the polymorphism between groups. Multiple regression analysis in 77 patients demonstrated that the rate of decline in renal function in terms of glomerular filtration rate was significantly correlated to the baseline level of cholesterol (P = 0.0014), mean diastolic blood pressure during follow-up period (P = 0.019), and baseline level of HbA1c (P = 0.022) adjusting for the effect of diabetes duration and gender, but no significant association was found between the polymorphism and the progression of diabetic nephropathy in our studied population. In summary, our results show that the PPARγ2 polymorphism is unlikely to be associated with the development and progression of the diabetic nephropathy in patients with type 1 diabetes. Further studies in different populations may be warranted to confirm our findings as the sample size in our study was relatively small.
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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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Abstract
Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this “missing heritability”, including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.
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Pereira AC, Oliveira R, Castro AC, Fernandes R. Does Pro(12)Ala Polymorphism Enhance the Physiological Role of PPARγ2? PPAR Res 2013; 2013:401274. [PMID: 23983677 PMCID: PMC3747383 DOI: 10.1155/2013/401274] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 06/29/2013] [Indexed: 11/28/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2D) are two major public health problems that have motivated the scientific community to investigate the high contribution of genetic factors to these disorders. The peroxisome proliferator activated by gamma 2 (PPARγ2) plays an important role in the lipid metabolism. Since PPARγ2 is expressed mainly in adipose tissue, a moderate reduction of its activity influences the sensitivity to insulin, diabetes, and other metabolic parameters. The present study aims to contribute to the elucidation of the impact of the Pro(12)Ala polymorphism associated with T2D and obesity through a meta-analysis study of the literature that included approximately 11500 individuals, from which 3870 were obese and 7625 were diabetic. Statistical evidence supports protective effect in T2D of polymorphism Pro(12)Ala of PPARγ2 (OR = 0.702 with 95% CI: 0.622; 0.791, P < 0.01). Conversely the same polymorphism Pro(12)Ala of PPARγ2 seems to favor obesity since 1.196 more chance than nonobese was found (OR = 1.196 with 95% CI: 1.009; 1.417, P < 0.004). Our results suggest that Pro(12)Ala polymorphism enhances both adipogenic and antidiabetogenic physiological role of PPARγ. Does Pro(12)Ala polymorphism represent an evolutionary step towards the stabilization of the molecular function of PPARγ transcription factor signaling pathway?
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Affiliation(s)
- A. C. Pereira
- Unit of Molecular Mechanisms of Disease (CISA) and Chemical and Biomolecular Sciences, School of Allied Health Sciences, Polytechnic Institute of Porto (ESTSP-IPP), Portugal
- Center of Pharmacology and Chemical Biopathology (U38-FCT), Medical Faculty, University of Porto, Portugal
| | - R. Oliveira
- Center for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, University of Porto, Portugal
- Biomathematics, Biostatistics and Bioinformatics, ESTSP-IPP, Porto, Portugal
| | - A. C. Castro
- Unit of Molecular Mechanisms of Disease (CISA) and Chemical and Biomolecular Sciences, School of Allied Health Sciences, Polytechnic Institute of Porto (ESTSP-IPP), Portugal
| | - R. Fernandes
- Unit of Molecular Mechanisms of Disease (CISA) and Chemical and Biomolecular Sciences, School of Allied Health Sciences, Polytechnic Institute of Porto (ESTSP-IPP), Portugal
- Center of Pharmacology and Chemical Biopathology (U38-FCT), Medical Faculty, University of Porto, Portugal
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Gu SJ, Liu MM, Guo ZR, Wu M, Chen Q, Zhou ZY, Zhang LJ, Luo WS. Gene–gene interactions among PPARα/δ/γ polymorphisms for hypertriglyceridemia in Chinese Han population. Gene 2013; 515:272-6. [DOI: 10.1016/j.gene.2012.11.078] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 10/27/2012] [Accepted: 11/27/2012] [Indexed: 01/01/2023]
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Correlation of peroxisome proliferator-activated receptor (PPAR-γ) mRNA expression with Pro12Ala polymorphism in obesity. Biochem Genet 2013; 51:256-63. [PMID: 23315125 DOI: 10.1007/s10528-012-9560-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 07/20/2012] [Indexed: 12/22/2022]
Abstract
Our study aimed to analyze whether the expression of PPARγ mRNA in subcutaneous adipocyte tissue correlates with Pro12Ala PPARγ2 polymorphism in the obesity context. We found that mRNA expression of PPARγ in subcutaneous adipose tissue was greater in obese subjects (P < 0.05) than in the nonobese control group. Concurrently, genotyping of the Pro12Ala polymorphism showed that obese subjects possess a significantly higher frequency of the Pro/Pro genotype than nonobese controls (90.5 vs 79.5%; P = 0.03), suggesting that this genotype is involved in an increased risk of obesity in the Tunisian population. Taken together, our results demonstrate that the Pro12 allele is accompanied by an overexpression of PPARγ mRNA in subcutaneous adipocyte tissue, suggesting that the PPARγ Pro12Ala variant may contribute to the observed variability in PPARγ mRNA expression and consequently in body mass index and insulin sensitivity in the general population.
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Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1090-5. [PMID: 22504298 DOI: 10.1016/j.bbadis.2012.03.014] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2011] [Revised: 03/26/2012] [Accepted: 03/27/2012] [Indexed: 12/14/2022]
Abstract
Adipocytes are highly specialized cells that play a central role in lipid homeostasis and the maintenance of energy balance. Obesity, an excessive accumulation of adipose tissue, is a major risk factor for the development of Type 2 diabetes mellitus (T2DM), cardiovascular disease, and hypertension. A variety of studies suggest that obesity and T2DM can be linked to a breakdown in the regulatory mechanisms that control the expression and transcriptional activity of PPARγ. PPARγ is a nuclear hormone receptor that functions as a master switch in controlling adipocyte differentiation and development. Also important in controlling glucose homeostasis and insulin sensitivity, PPARγ is a ligand-dependent transcription factor that is the functional receptor for the anti-diabetic thiazolidinediones (TZDs). In the last fifteen years, a variety of covalent modifications of PPARγ activity have been identified and studied. These covalent modifications include phosphorylation, ubiquitylation, O-GlcNAcylation and SUMOylation. Covalent modifications of PPARγ represent key regulatory mechanisms that control both PPARγ protein stability and transcriptional activity. A variety of PPARγ transgenic models, including mice heterozygous for PPARγ, have demonstrated the importance of PPARγ expression in glucose homeostasis and insulin resistance. In the following review, we have highlighted the regulation of PPARγ by covalent modifications, the interplay between these interactions and how these post-translational modifications impact metabolic disease states.
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Nazih H, Raffi F, Taïeb A, Reynes J, Choutet P, Cassuto JP, Ferry T, Chêne G, Leport C, Bard, for the APROCO-COPILOTE (ANRS JM. Peroxisome proliferator activating receptor alpha and gamma polymorphisms and metabolic abnormalities in HIV-infected patients receiving highly active antiretroviral therapy: the ANRS CO8 APROCO-COPILOTE study. AIDS Res Hum Retroviruses 2012; 28:393-9. [PMID: 21877956 DOI: 10.1089/aid.2010.0311] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Highly active antiretroviral therapy (HAART) is associated with fat redistribution and metabolic disorders. The present study was undertaken to evaluate the association between peroxisome proliferator activated receptor (PPAR)α and PPARγ polymorphisms, two genes involved in lipid metabolism and adipocyte differentiation, and elements of the metabolic syndrome, lipodystrophy, or carbohydrate metabolism abnormalities in patients receiving HAART. The frequency distribution of rare alleles for PPARα (L162V) and PPARγ (P12A and H449H) was compared using the chi square test in 363 HIV-1-infected patients classified according to the presence or absence of the metabolic syndrome after 48 months of follow-up on their first PI-containing regimen. The P12A rare g allele was present in 12% patients with normal glucose metabolism, 11% patients with impaired glucose tolerance or impaired fasting glucose, and 35% patients with diabetes (p=0.014). The rare g allele for L162V was present in 14% of patients free of hypertriglyceridemia and in 7% patients with hypertriglyceridemia (p=0.04). The rare g allele for L162V was found in 15% of patients free of any sign of lipodystrophy and 8% with at least one sign of lipodystrophy (p=0.04) and the rare t allele for H449H was found in 14% of patients free of any sign of lipodystrophy and 23% of patients with at least one sign of lipodystrophy (p=0.05). There was no convincing association between any polymorphism of PPARα and PPARγ and each individual component of the metabolic syndrome, except for the relationship of the P12A polymorphism with diabetes. Confirmatory studies on a larger number of individuals are needed.
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Affiliation(s)
| | | | | | - Jacques Reynes
- Service des maladies infectieuses, CHU, Montpellier, France
| | | | | | - Tristan Ferry
- Service des maladies infectieuses, CHU, Lyon, France
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Anbalagan M, Huderson B, Murphy L, Rowan BG. Post-translational modifications of nuclear receptors and human disease. NUCLEAR RECEPTOR SIGNALING 2012; 10:e001. [PMID: 22438791 PMCID: PMC3309075 DOI: 10.1621/nrs.10001] [Citation(s) in RCA: 159] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Accepted: 08/19/2011] [Indexed: 12/12/2022]
Abstract
Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.
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Affiliation(s)
- Muralidharan Anbalagan
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
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Pro12Ala polymorphism in human peroxisome proliferator activated receptor gamma is associated with hyperlipidaemia in obstructive sleep apnoea hypopnoea syndrome. The Journal of Laryngology & Otology 2011; 125:1042-8. [DOI: 10.1017/s002221511100123x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AbstractObjective:Peroxisome proliferator activated receptor gamma is a ligand-dependent transcription factor with an important role in insulin resistance and obesity. We investigated the associations between the Pro12Ala polymorphism of this receptor, obstructive sleep apnoea hypopnoea syndrome and hyperlipidaemia risk factors, in a Chinese cohort.Subjects and methods:We recruited 420 obstructive sleep apnoea hypopnoea syndrome patients and 190 healthy controls. Genetic analysis was conducted by restriction fragment length polymorphism. The hyperlipidaemia risk in both the study and control groups was analysed.Results:Comparison of genotype and allele frequencies revealed no significant differences between patients and controls (p > 0.05). In patients, there was no correlation between genotype and clinical parameters (p > 0.05), apart from a significant association between the Ala12 allele and hyperlipidaemia (odds ratio = 2.181; p = 0.017; 95 per cent confidence interval = 1.133–4.198).Conclusion:In this Chinese cohort, the Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma was not associated with obstructive sleep apnoea hypopnoea syndrome, but was associated with increased hyperlipidaemia risk.
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Jermendy A, Körner A, Kovács M, Madácsy L, Cseh K. PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity. J Pediatr Endocrinol Metab 2011; 24:55-9. [PMID: 21528816 DOI: 10.1515/jpem.2011.111] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. METHODS In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. RESULTS The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF-alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. CONCLUSIONS The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism.
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Affiliation(s)
- Agnes Jermendy
- 1st Department of Paediatrics, Semmelweis University, Budapest, Hungary.
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Razquin C, Marti A, Martinez JA. Evidences on three relevant obesogenes: MC4R, FTO and PPARγ. Approaches for personalized nutrition. Mol Nutr Food Res 2010; 55:136-49. [PMID: 21207518 DOI: 10.1002/mnfr.201000445] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 11/05/2010] [Accepted: 11/05/2010] [Indexed: 11/09/2022]
Abstract
Obesity is a complex disease that results from the interaction between lifestyle (dietary patterns and sedentary habits) and genetic factors. The recognition of a genetic basis for human obesity has driven to identify putative causal genes to understand the pathways that control body mass and fat deposition in humans as well as to provide personalized treatments and prevention strategies to fight against obesity. More than 120 candidate genes have been associated with obesity-related traits. Genome-wide association study has so far identified over 20 novel loci convincingly associated with adiposity. This review is specifically focused on the study of the effects of melanocortin 4 receptor, Peroxisome proliferator-activated receptor γ and fat mass and obesity associated (FTO) gene variants and their interactions with dietary intake, physical activity or drug administration on body weight control. The advances in this field are expected to open new ways in genome-customized diets for obesity prevention and therapy following personalized approaches.
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Affiliation(s)
- Cristina Razquin
- Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Irunlarrea 1, Pamplona, Navarra, Spain
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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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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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Jeninga EH, Gurnell M, Kalkhoven E. Functional implications of genetic variation in human PPARgamma. Trends Endocrinol Metab 2009; 20:380-7. [PMID: 19748282 DOI: 10.1016/j.tem.2009.04.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2009] [Revised: 04/15/2009] [Accepted: 04/15/2009] [Indexed: 12/25/2022]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of lipid and glucose metabolism. Human genetic evidence supporting this view comes from the study of both common (e.g. the Pro12Ala polymorphism) and rare (loss-of-function mutations) variants in the gene encoding PPARgamma. Indeed, patients harbouring mutant PPARgamma exhibit familial partial lipodystrophy type 3 and an extreme monogenic form of the metabolic syndrome. The recent elucidation of the crystal structure of the full-length PPARgamma-RXRalpha heterodimer bound to DNA has shed new light on the functional consequences of these genetic PPARgamma alterations and provides novel insights as to why different perturbations of receptor function unite in a common pathway of metabolic dysfunction.
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Affiliation(s)
- Ellen H Jeninga
- Department of Metabolic and Endocrine Diseases, UMC Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands
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Mirzaei H, Akrami SM, Golmohammadi T, Doosti M, Heshmat R, Nakhjavani M, Amiri P. Polymorphism of Pro12Ala in the Peroxisome Proliferator-Activated Receptor γ2 Gene in Iranian Diabetic and Obese Subjects. Metab Syndr Relat Disord 2009; 7:453-8. [DOI: 10.1089/met.2008.0099] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Hassan Mirzaei
- Department of Hygiene, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Clinical Biochemistry, School of Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Akrami
- Endocrinology and Metabolism Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Medical Genetics Department, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Taghi Golmohammadi
- Department of Clinical Biochemistry, School of Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Doosti
- Department of Clinical Biochemistry, School of Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- Endocrinology and Metabolism Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvin Amiri
- Endocrinology and Metabolism Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Leslie RDG, Cohen RM. Biologic variability in plasma glucose, hemoglobin A1c, and advanced glycation end products associated with diabetes complications. J Diabetes Sci Technol 2009; 3:635-43. [PMID: 20144305 PMCID: PMC2769979 DOI: 10.1177/193229680900300403] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Plasma glucose plays a key role in the complications of diabetes mellitus. Hemoglobin A1c (HbA1c) and circulating concentrations of advanced glycation end products (AGEs) are central to diabetes clinical care and pathophysiology. However, there is evidence for variation between individuals in the relationship of plasma glucose to both these measures and to specific complications. The glycation gap (GG) and hemoglobin glycation index represent tools for quantitating the variability in the relationship between plasma glucose and HbA1c useful for identification of underlying mechanisms. Recent evidence demonstrates the heritability of HbA1c, the GG, and AGEs, yet not of glycated serum proteins. There has been tremendous effort devoted to identifying the heritable basis of types 1 and 2 diabetes; however, studies on the heritable contributors to these mediators of glucose effect on complications are only beginning. New evidence for normal biologic variation in the distribution of glucose into the red blood cell (RBC) intracellular compartment and RBC lifespan in people with and without diabetes represent candidates for heritable mechanisms and contributors to the rise in HbA1c with age. Taken as a whole, genetic and mechanistic evidence suggests new potential targets for complications prevention and improvement in complications risk estimation. These observations could help tilt the risk-benefit balance in glycemic control toward a more beneficial outcome.
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Affiliation(s)
- R. David G. Leslie
- Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St. Bartholomew's Hospital, London, United Kingdom
| | - Robert M. Cohen
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio
- Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
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Effect of the Pro12Ala polymorphism of the PPAR gamma 2 gene on response to pioglitazone treatment in menopausal women. Menopause 2009; 15:1151-6. [PMID: 18551086 DOI: 10.1097/gme.0b013e31816d5b2d] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To investigate the influence of the Pro12Ala polymorphism of the PPAR gamma 2 gene on metabolic and hormonal response to pioglitazone treatment in obese postmenopausal women. DESIGN We included 102 obese (body mass index [BMI] >or=30 kg/m2) and 97 nonobese (BMI <or=27 kg/m2) postmenopausal women. Anthropometric data were collected, and fasting glucose, insulin, leptin, follicle-stimulating hormone, luteinizing hormone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, estrone, estradiol, and adiponectin were measured and the PPAR gamma 2 Pro12Ala genotypes were determined. Eighty-three obese postmenopausal women were treated with pioglitazone 15 mg/day for 15 days, and hormone levels and insulin resistance (homeostasis model assessment of insulin resistance) were assessed before and after treatment. RESULTS Obese women had a higher BMI, waist-to-hip ratio, fasting glucose, insulin, homeostasis model assessment of insulin resistance, leptin, dehydroepiandrosterone, estradiol, testosterone, and adiponectin levels, whereas the follicle-stimulating hormone level was lower. Genotype frequencies were similar in obese and nonobese women. Analysis of the whole group showed that women with the Pro/Ala genotype had a higher BMI, waist-to-hip ratio, and fasting glucose (P < 0.04, P < 0.02, and P < 0.004, respectively) than the group with the Pro/Pro genotype. After pioglitazone treatment, glucose levels decreased in both genotypes, but at a greater amount in carriers of the Pro/Ala genotype (-15 mg/dL vs -7 mg/dL, P < 0.003). However, insulin and homeostasis model assessment of insulin resistance levels were lower in carriers of the Pro/Pro genotype (-4.0 vs 0.7 IU/L, P=0.009 and -1.0 vs -0.08, P = 0.03, respectively). CONCLUSIONS The Pro/Ala genotype of PPAR gamma 2 was associated with obesity and higher fasting glucose. Pioglitazone treatment in obese women with the Pro/Ala genotype induced a greater glucose decrease, and obese women may derive more benefit from this drug.
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van Beekum O, Fleskens V, Kalkhoven E. Posttranslational modifications of PPAR-gamma: fine-tuning the metabolic master regulator. Obesity (Silver Spring) 2009; 17:213-9. [PMID: 19169221 DOI: 10.1038/oby.2008.473] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Olivier van Beekum
- Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands
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Abstract
Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARgamma agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARgamma in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARgamma modulators.
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Affiliation(s)
- Silvia I Anghel
- Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne CH-1015, Switzerland
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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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Ochoa MC, Razquin C, Martinez-Gonzalez MÁ, Marti A, Martinez JA. Role of PPAR-γ2 polymorphisms in bodyweight regulation. ACTA ACUST UNITED AC 2008. [DOI: 10.2217/17460875.3.1.31] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Anghel SI, Bedu E, Vivier CD, Descombes P, Desvergne B, Wahli W. Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma. J Biol Chem 2007; 282:29946-57. [PMID: 17699161 DOI: 10.1074/jbc.m702490200] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPARgamma allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma. It is likely that the PPARgamma(+/-) phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health.
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Affiliation(s)
- Silvia I Anghel
- Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Génopode Bldg., CH-1015 Lausanne, Switzerland
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Nelson TL, Fingerlin TE, Moss L, Barmada MM, Ferrell RE, Norris JM. The PPARγ Pro12Ala Polymorphism Is Not Associated with Body Mass Index or Waist Circumference among Hispanics from Colorado. ANNALS OF NUTRITION AND METABOLISM 2007; 51:252-7. [DOI: 10.1159/000104145] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2006] [Accepted: 12/27/2006] [Indexed: 11/19/2022]
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Meshkani R, Taghikhani M, Larijani B, Bahrami Y, Khatami S, Khoshbin E, Ghaemi A, Sadeghi S, Mirkhani F, Molapour A, Adeli K. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population. Clin Chem Lab Med 2007; 45:477-82. [PMID: 17439324 DOI: 10.1515/cclm.2007.095] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene has been variably associated with insulin resistance, obesity and type 2 diabetes in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that this variation might be associated with insulin resistance, type 2 diabetes and related metabolic traits in this population. METHODS The Pro12Ala genotypes were determined by PCR-restriction fragment length polymorphism in 696 unrelated subjects including 412 non-diabetic controls and 284 type 2 diabetic patients. RESULTS The frequency of the Ala allele was 9.4% and 5.9% in controls and type 2 diabetic subjects, respectively [adjusted odds ratio (OR) 0.457, p=0.005]. The Ala allele did not show a significant effect on anthropometric and biochemical parameters in the type 2 diabetic group, whereas in non-diabetic subjects, carriers of the Ala allele had significantly lower fasting insulin (p=0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (p=0.009) levels compared to Pro/Pro subjects. Multivariate logistic regression analysis showed that Pro12Ala polymorphism was an independent determinant of type 2 diabetes in this population. CONCLUSIONS Our results for a sample of Iranian type 2 diabetes cases and controls provide evidence that the Pro/Ala genotype of the PPARgamma-2 gene is associated with insulin sensitivity and may also have protective role against type 2 diabetes.
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Affiliation(s)
- Reza Meshkani
- Endocrinology and Metabolism Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Ludovico O, Pellegrini F, Di Paola R, Minenna A, Mastroianno S, Cardellini M, Marini MA, Andreozzi F, Vaccaro O, Sesti G, Trischitta V. Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk. Obesity (Silver Spring) 2007; 15:1076-81. [PMID: 17495182 DOI: 10.1038/oby.2007.617] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Conflicting results have been reported regarding whether the PPARgamma2 Pro12Ala polymorphism plays a role in the risk of type 2 diabetes (T2D), suggesting genetic heterogeneity. To investigate this issue, a meta-analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted. Ala12 carriers had a 19% T2D risk reduction, but this association was highly heterogeneous (p = 0.005). A great proportion (48%) of heterogeneity was explained by the controls' BMI, with risk reduction being greater when BMI was lower. Risk reduction of Ala12 carriers in Asia (35%) was higher than in Europe (15%, p = 0.02) and tended to be higher than in North America (18%, p = 0.10). Difference between Asians and Europeans was no longer significant (p = 0.15) after adjusting for the controls' BMI. Studies from Europe were still heterogeneous (p = 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p = 0.02) from Northern (26% reduction, p < 0.0001) to Central (10%, p = 0.04) and Southern (0%, p = 0.94) Europe. In conclusion, in our meta-analysis, the reduced risk of T2D in Ala12 carriers is not homogeneous. It is greater in Asia than in Europe and, among Europeans, it is higher in Northern Europe, barely significant in Central Europe, and nonexistent in Southern Europe.
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Affiliation(s)
- Ornella Ludovico
- Unit of Endocrinology, Scientific Institute "Casa Sollievo della Sofferenza," Viale Cappuccini, S. Giovanni Rotondo, 71013 Italy.
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Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuler D. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab 2007; 92:1502-9. [PMID: 17213274 PMCID: PMC2267936 DOI: 10.1210/jc.2006-2275] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes. OBJECTIVE We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo). PATIENTS This study included 3548 Diabetes Prevention Program participants. DESIGN We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr. RESULTS Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99-1.57; P=0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P=0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr. CONCLUSIONS The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.
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Affiliation(s)
- Jose C Florez
- Center for Human Genetic Research and Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston 02114, USA.
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Zollner S, Pritchard JK. Overcoming the winner's curse: estimating penetrance parameters from case-control data. Am J Hum Genet 2007; 80:605-15. [PMID: 17357068 PMCID: PMC1852705 DOI: 10.1086/512821] [Citation(s) in RCA: 279] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2006] [Accepted: 01/08/2007] [Indexed: 11/03/2022] Open
Abstract
Genomewide association studies are now a widely used approach in the search for loci that affect complex traits. After detection of significant association, estimates of penetrance and allele-frequency parameters for the associated variant indicate the importance of that variant and facilitate the planning of replication studies. However, when these estimates are based on the original data used to detect the variant, the results are affected by an ascertainment bias known as the "winner's curse." The actual genetic effect is typically smaller than its estimate. This overestimation of the genetic effect may cause replication studies to fail because the necessary sample size is underestimated. Here, we present an approach that corrects for the ascertainment bias and generates an estimate of the frequency of a variant and its penetrance parameters. The method produces a point estimate and confidence region for the parameter estimates. We study the performance of this method using simulated data sets and show that it is possible to greatly reduce the bias in the parameter estimates, even when the original association study had low power. The uncertainty of the estimate decreases with increasing sample size, independent of the power of the original test for association. Finally, we show that application of the method to case-control data can improve the design of replication studies considerably.
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Affiliation(s)
- Sebastian Zollner
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
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Roche HM, Phillips C, Gibney MJ. The metabolic syndrome: the crossroads of diet and genetics. Proc Nutr Soc 2007; 64:371-7. [PMID: 16048671 DOI: 10.1079/pns2005445] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The metabolic syndrome is a very common disease associated with an increased risk of type 2 diabetes mellitus (T2DM) and CVD. The clinical characteristics of the metabolic syndrome include insulin resistance, dyslipidaemia, abdominal obesity and hypertension. The diverse clinical characteristics illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the metabolic syndrome. Nevertheless, the human genome has not changed markedly in the last decade but the prevalence of the metabolic syndrome has increased exponentially, which illustrates the importance of gene–environmental interactions. There is good evidence that nutrition plays an important role in the development and progression of the metabolic syndrome. Indeed, obesity is a key aetiological factor in the development of the metabolic syndrome. Understanding the biological impact of gene–nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the metabolic syndrome. The present paper will explore the interactions between genetic background and dietary exposure or nutritional therapy, focusing on the role of dietary fatty acids within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. Only with a full understanding of gene–gene, gene–nutrient and gene–nutrient–environment interactions can the molecular basis of the metabolic syndrome be solved to minimise the adverse health effects of obesity and reduce the risk of the metabolic syndrome, and subsequent T2DM and CVD.
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Affiliation(s)
- Helen M Roche
- Nutrigenomics Research Group, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Republic of Ireland.
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Rhee EJ, Kwon CH, Lee WY, Kim SY, Jung CH, Kim BJ, Sung KC, Kim BS, Oh KW, Kang JH, Park SW, Kim SW, Lee MH, Park JR. No Association of Pro12Ala Polymorphism of PPAR-.GAMMA. Gene With Coronary Artery Disease in Korean Subjects. Circ J 2007; 71:338-42. [PMID: 17322631 DOI: 10.1253/circj.71.338] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-gamma was investigated in Korean adults. METHODS AND RESULTS The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD. CONCLUSIONS There was no significant association between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future.
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Affiliation(s)
- Eun Jung Rhee
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea
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Tönjes A, Scholz M, Loeffler M, Stumvoll M. Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with Pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals. Diabetes Care 2006; 29:2489-97. [PMID: 17065690 DOI: 10.2337/dc06-0513] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The provariant of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)gamma has been identified as a risk allele for type 2 diabetes. The purpose of the present study was to reveal a significant association with pre-diabetic phenotypes in nondiabetic individuals based on a systematic meta-analysis of all available published evidence. RESEARCH DESIGN AND METHODS We performed a classical meta-analysis of data from approximately 32,000 nondiabetic subjects in 57 studies to assess the effect of the Pro12Ala polymorphism on pre-diabetic traits. RESULTS In the global comparison, there were no differences in BMI, glucose, insulin, or homeostasis model assessment of insulin resistance between the Pro/Pro and X/Ala genotype. However, in the Caucasian subgroup, the X/Ala genotype was associated with significantly increased BMI. In the obese subgroup (BMI >30 kg/m(2)), fasting glucose (P = 0.041) and insulin resistance (by homeostasis model analysis) (P = 0.020) were significantly greater in the Pro/Pro group. In subjects with the homozygous Ala/Ala genotype, fasting insulin was significantly lower compared with the Pro/Pro genotype (P = 0.040, N(Ala/Ala) = 154). CONCLUSIONS Across all studies, the Pro12Ala polymorphism had no significant effect on diabetes-related traits. Only in selected subgroups, such as Caucasians and obese subjects, did we see an association of the Ala allele with greater BMI and greater insulin sensitivity. This demonstrates the importance for appropriate stratification of analyses by environmental or other genetic factors. Meta-analysis of Ala/Ala homozygotes more clearly demonstrated the association with greater insulin sensitivity of carriers of the Ala allele.
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Affiliation(s)
- Anke Tönjes
- University of Leipzig, IIIrd Medical Department, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany
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Yaffe K, Kanaya AM, Lindquist K, Hsueh WC, Cummings SR, Beamer B, Newman A, Rosano C, Li R, Harris T. PPAR-gamma Pro12Ala genotype and risk of cognitive decline in elders. Neurobiol Aging 2006; 29:78-83. [PMID: 17052804 PMCID: PMC2233891 DOI: 10.1016/j.neurobiolaging.2006.09.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2006] [Revised: 08/03/2006] [Accepted: 09/13/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been associated with decreased risk of diabetes and obesity, both disorders linked to cognitive impairment. We tested whether this polymorphism is associated with cognition. METHODS Two thousand nine hundred sixty-one participants (mean age, 74.1; 41% Black; 52% women) were administered the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and 4 year follow-up. Test scores were adjusted for age, sex, education, cerebrovascular disease, depression and APOE genotype and additionally for race. We determined the association between Ala allele and development of cognitive decline (3MS decline of > or = 5 points). RESULTS At baseline, unadjusted scores on both cognitive tests were higher for Ala carriers compared to non-carriers (3MS, 94.2 versus 92.5, p<0.001; DSST, 40.2 versus 34.5, p<0.001). Similarly, follow-up scores were higher for Ala carriers. Multivariable adjustment led to similar results; additional adjustment for race attenuated the baseline 3MS results. After 4 years, 17.5% of Ala carriers developed cognitive decline compared to 25% among non-carriers (unadjusted OR=0.61; 95%CI, 0.46-0.82; adjusted OR=0.75; 95%CI, 0.55-1.02). Further adjustment for metabolic variables including fasting blood glucose and lipid level did not change the results. CONCLUSIONS The PPAR-gamma Ala12 allele carriers may have less risk of developing cognitive decline.
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Affiliation(s)
- K Yaffe
- Department of Psychiatry and Neurology, University of California, San Francisco, CA 94121, United States.
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Rhee EJ, Oh KW, Lee WY, Kim SY, Oh ES, Baek KH, Kang MI, Kim SW. Effects of two common polymorphisms of peroxisome proliferator-activated receptor-gamma gene on metabolic syndrome. Arch Med Res 2006; 37:86-94. [PMID: 16314192 DOI: 10.1016/j.arcmed.2005.04.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2005] [Accepted: 04/19/2005] [Indexed: 12/30/2022]
Abstract
BACKGROUND Peroxisome proliferator-activated receptor (PPAR)gamma is involved mainly in adipocyte differentiation and has been suggested to play an important role in the pathogenesis of insulin resistance and atherosclerosis. We investigated the frequencies of two common polymorphisms of PPARgamma gene, exon 6 C-->T substitution and exon B Pro12Ala in healthy subjects and analyzed the correlations between the different genotypes and insulin resistance, metabolic syndrome and cardiovascular risk factors. METHODS Anthropometric measurements, fasting glucose, insulin and lipid profiles were measured in 253 Korean females. Homeostatic model assessments and quantitative insulin sensitivity check indices were calculated. Metabolic syndrome was diagnosed according to the NCEP-ATP III guidelines and the Western Pacific Region of WHO for obesity criteria for waist circumference. Polymerase chain reaction (PCR)-restriction fragment-length polymorphism and real-time PCR were performed for genotyping of the DNAs. RESULTS For C161T polymorphism, allele frequencies were 0.804 and 0.196 for T allele, and 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, fasting blood glucose level, fasting insulin levels, HOMA and QUICKI among different genotypes when analyzed as a whole, except that subjects with Pro12Ala had significantly higher body weight than those with Pro12Pro genotype. However, mean BMI, percent body fat and weight showed significant differences between genotypes in younger age group (< or =50 years). Although overall prevalence of metabolic syndrome had no association with the genotypes, the prevalence of decreased high-density lipoprotein cholesterol component was lower in those with the T allele than in those with the CC genotype. There was no association of the genotypes with glucose tolerance status. When the subjects were divided into four groups according to the combination of the genetic alleles of the two polymorphisms, subjects having Pro12Ala and T allele, simultaneously, showed significantly higher mean weight than those without Ala allele. Pro12Ala polymorphism seems to affect body weight, similar to the previous studies, and the effect was potentiated with the presence of T allele of C161T polymorphism. CONCLUSIONS Although either polymorphism failed to show significant association with insulin resistance, the fact that the prevalence of decreased HDL-C was lower in those with the T allele of C161T polymorphism suggests that this polymorphism might have a protective effect on atherosclerotic lipid profiles, which needs further investigation.
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Affiliation(s)
- Eun Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Gurnell M. Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies. Best Pract Res Clin Endocrinol Metab 2005; 19:501-23. [PMID: 16311214 DOI: 10.1016/j.beem.2005.10.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
In recent years, the thiazolidinediones (e.g. rosiglitazone, pioglitazone) have emerged as an exciting novel class of therapeutic agent for the treatment of type 2 diabetes mellitus and the human metabolic syndrome. At first glance, the use of these high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, that promote adipogenesis, to treat a group of disorders that typically have their origins in obesity seems counter-intuitive. However, to view PPARgamma simply as a regulator of fat mass, and adipocytes themselves as passive vessels for energy storage, is to ignore an extensive body of data that speaks of the diverse roles of both this receptor and adipose tissue in the maintenance of normal metabolic homeostasis. This article highlights the important clinical and laboratory observations made in human subjects harbouring genetic variations in PPARgamma that have confirmed its pivotal role in the regulation of adipocyte endocrine function, and thus our metabolic response to the environment.
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Affiliation(s)
- Mark Gurnell
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, UK.
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Tavares V, Hirata RDC, Rodrigues AC, Monte O, Salles JEN, Scalissi N, Speranza AC, Hirata MH. Association between Pro12Ala polymorphism of the PPAR-gamma2 gene and insulin sensitivity in Brazilian patients with type-2 diabetes mellitus. Diabetes Obes Metab 2005; 7:605-11. [PMID: 16050954 DOI: 10.1111/j.1463-1326.2004.00453.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM Peroxisome-proliferator-activated receptor-gamma2 (PPAR-gamma2) is a nuclear receptor that plays an important role in lipid metabolism and insulin sensitivity. The purpose of this study is to investigate the association of Pro12Ala polymorphism at the PPAR-gamma2 gene in Brazilian patients with type-2 diabetes mellitus (T2Dm) and controls (CG). METHODS Genomic DNA was obtained from 207 unrelated white people presenting with T2Dm and from 170 controls. Anthropometric data included body mass index and waist to hip ratio. Biochemical parameters included fasting plasma glucose, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, glycated haemoglobin and insulin. Systolic and diastolic blood pressures were also measured. Screening for mutations in the entire coding region of the PPAR-gamma gene was performed by means of polymerase chain reaction (PCR), single-strand conformational polymorphism and sequencing. Pro12Ala polymorphism was analysed by using PCR-RFLP (restriction fragment-length polymorphism). RESULTS One base substitution was identified - a C to G substitution in exon B of the PPAR-gamma2 gene. The frequency of the Ala12 allele in T2Dm (0.09) was similar to that found in CG (0.06, p = 0.185). In the T2Dm group, Ala12 allele was associated with lower fasting plasma insulin levels (p = 0.036) and higher insulin sensitivity (p = 0.049) by means of homeostasis model assessment. Among obese people, there was no association between any of the T2Dm or obesity-related traits and the Pro12Ala polymorphism. CONCLUSIONS The results of our study suggest that people with the Ala12 allele of the PPAR-gamma2 gene could be more sensitive to insulin than those carriers of the Pro12 allele among Brazilian Caucasians.
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Affiliation(s)
- V Tavares
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
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