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Song J, Zhuang Y, Pan X, Chen Y, Xie F. Variants in PPARD- GLP1R are related to diabetic kidney disease in Chinese Han patients with type 2 diabetes mellitus. Heliyon 2024; 10:e35289. [PMID: 39161836 PMCID: PMC11332863 DOI: 10.1016/j.heliyon.2024.e35289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 07/22/2024] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
Genetic susceptibility is an important pathogenic mechanism in diabetic kidney disease (DKD). Our previous studies have identified that PPARδ and GLP-1R are located in a pathway that is closely related to DKD. We aimed to explore the impacts of variants in PPARD-GLP1R on the susceptibility to DKD in Chinese Han patients with type 2 diabetes mellitus (T2DM). A total of 600 T2DM patients (300 with DKD and 300 without DKD) and 200 healthy control subjects were enrolled to identify PPARD (rs2016520, rs2267668 and rs3777744) and GLP1R (rs3765467, rs1042044 and rs9296291) genotype. The SNaPshot method was used to identify variants in PPARD-GLP1R. We performed correlation analysis between variants in PPARD-GLP1R and the susceptibility to DKD. We observed that GLP1R rs3765467 (G > A) was associated with DKD (OR = 3.145, 95 % CI = 2.128-6.021, P = 0.035). None of the other SNPs were associated with DKD. Regarding DKD related traits, rs3765467 was associated with UACR levels and TC, significant differences were observed among patients with different genotypes of rs2016520 in terms of BMI and TG, and patients with the rs3777744 risk G allele had noticeably higher PPG and HbA1c levels (P < 0.05). Moreover, the results showed the interactions between PPARD rs3777744 and GLP1R rs3765467 in the occurrence of DKD (OR = 4.572, P = 0.029). The results of this study indicate the potential relationship between variants in PPARD-GLP1R and the susceptibility to DKD in Chinese Han patients with T2DM.
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Affiliation(s)
- Jinfang Song
- Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221000, China
| | - Yongru Zhuang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221000, China
| | - Xiaojun Pan
- Department of Pharmacy, Wuxi No.5 People's Hospital, Wuxi, 214000, China
| | - Ya Chen
- Department of Endocrinology, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
| | - Fen Xie
- Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China
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Reza-López SA, González-Gurrola S, Morales-Morales OO, Moreno-González JG, Rivas-Gómez AM, González-Rodríguez E, Moreno-Brito V, Licón-Trillo A, Leal-Berumen I. Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-β/δ Polymorphisms. Biomolecules 2023; 13:1791. [PMID: 38136661 PMCID: PMC10741495 DOI: 10.3390/biom13121791] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. OBJECTIVE To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). MATERIALS AND METHODS We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-β/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. RESULTS minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-β/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. CONCLUSIONS PPAR-γ2 rs1801282 and PPAR-β/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.
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Affiliation(s)
- Sandra A. Reza-López
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Susana González-Gurrola
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Oscar O. Morales-Morales
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Janette G. Moreno-González
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Ana M. Rivas-Gómez
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Everardo González-Rodríguez
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Verónica Moreno-Brito
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Angel Licón-Trillo
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Irene Leal-Berumen
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
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Antar SA, Ashour NA, Sharaky M, Khattab M, Ashour NA, Zaid RT, Roh EJ, Elkamhawy A, Al-Karmalawy AA. Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments. Biomed Pharmacother 2023; 168:115734. [PMID: 37857245 DOI: 10.1016/j.biopha.2023.115734] [Citation(s) in RCA: 98] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 10/21/2023] Open
Abstract
Nowadays, diabetes mellitus has emerged as a significant global public health concern with a remarkable increase in its prevalence. This review article focuses on the definition of diabetes mellitus and its classification into different types, including type 1 diabetes (idiopathic and fulminant), type 2 diabetes, gestational diabetes, hybrid forms, slowly evolving immune-mediated diabetes, ketosis-prone type 2 diabetes, and other special types. Diagnostic criteria for diabetes mellitus are also discussed. The role of inflammation in both type 1 and type 2 diabetes is explored, along with the mediators and potential anti-inflammatory treatments. Furthermore, the involvement of various organs in diabetes mellitus is highlighted, such as the role of adipose tissue and obesity, gut microbiota, and pancreatic β-cells. The manifestation of pancreatic Langerhans β-cell islet inflammation, oxidative stress, and impaired insulin production and secretion are addressed. Additionally, the impact of diabetes mellitus on liver cirrhosis, acute kidney injury, immune system complications, and other diabetic complications like retinopathy and neuropathy is examined. Therefore, further research is required to enhance diagnosis, prevent chronic complications, and identify potential therapeutic targets for the management of diabetes mellitus and its associated dysfunctions.
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Affiliation(s)
- Samar A Antar
- Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt
| | - Nada A Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Marwa Sharaky
- Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Muhammad Khattab
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, Egypt
| | - Naira A Ashour
- Department of Neurology, Faculty of Physical Therapy, Horus University, New Damietta 34518, Egypt
| | - Roaa T Zaid
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt
| | - Eun Joo Roh
- Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Ahmed Elkamhawy
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
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Li S, Zhang Y, Xu W, Lv Z, Xu L, Zhao Z, Zhu D, Song Y. C Allele of the PPARδ+294T>C Polymorphism Confers a Higher Risk of Hypercholesterolemia, but not Obesity and Insulin Resistance: A Systematic Review and Meta-Analysis. Horm Metab Res 2023; 55:355-366. [PMID: 37011890 DOI: 10.1055/a-2043-7707] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
The relationships of the PPARα Leu162Val and PPARδ+294 T>C polymorphisms with metabolic indexes have been reported to be inconsistent and even contradictory. The meta-analysis was conducted to clarify the relationships between the two variants and the indexes of obesity, insulin resistance, and blood lipids. PubMed, Google Scholar, Embase, and Cochrane Library were searched for eligible studies. Standardized mean difference with 95% confidence interval was calculated to estimate the differences in the metabolic indexes between the genotypes of the Leu162Val and+294 T>C polymorphisms. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. Forty-one studies (44 585 subjects) and 33 studies (23 018 subjects) were identified in the analyses for the Leu162Val and+294 T>C polymorphisms, respectively. C allele carriers of the+294 T>C polymorphism had significantly higher levels of total cholesterol and low-density lipoprotein cholesterol than TT homozygotes in the whole population. Notably, C allele carriers of the+294 T>C polymorphism had significantly higher levels of triglycerides and total cholesterol in East Asians, but lower levels of triglycerides in West Asians than TT homozygotes. Regarding the Leu162Val polymorphism, it was found that Val allele carriers had significantly higher levels of blood glucose than Leu/Leu homozygotes only in European Caucasians. The meta-analysis demonstrates that C allele of the+294 T>C polymorphism in PPARδ gene confers a higher risk of hypercholesterolemia, which may partly explain the relationship between this variant and coronary artery disease.
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Affiliation(s)
- Shujin Li
- Central Laboratory, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, China
| | - Youjin Zhang
- Central Laboratory, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, China
| | - Wenhao Xu
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Zhimin Lv
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Luying Xu
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Zixuan Zhao
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Dan Zhu
- Clinical Medical College of Chengdu University, Chengdu, China
| | - Yongyan Song
- Central Laboratory, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, China
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Arif A, Alameri AA, Tariq UB, Ansari SA, Sakr HI, Qasim MT, Aljoborae FFM, Ramírez-Coronel AA, Jabbar HS, Gabr GA, Mirzaei R, Karampoor S. The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. Int Immunopharmacol 2023; 114:109581. [PMID: 36527874 DOI: 10.1016/j.intimp.2022.109581] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.
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Affiliation(s)
- Anam Arif
- Department of Government DHQ hospital Narowal, Gujranwala medical college, Gujranwala, Pakistan
| | - Ameer A Alameri
- Department of Chemistry, College of Science, University of Babylon, Babylon, Iraq
| | | | - Shakeel Ahmed Ansari
- Department of Biochemistry, Batterjee Medical College for Science and Technology, Jeddah, Saudi Arabia
| | - Hader Ibrahim Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Egypt; Department of Medical Physiology, Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Fadhil F M Aljoborae
- Department of Anesthesia Techniques, Al-Mustaqbal University College, Babylon, Iraq
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador
| | - Hijran Sanaan Jabbar
- Department of Chemistry, College of Science, Salahaddin University, Erbil, Iraq; Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Erbil, Iraq
| | - Gamal A Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Maciejewska-Skrendo A, Massidda M, Tocco F, Leźnicka K. The Influence of the Differentiation of Genes Encoding Peroxisome Proliferator-Activated Receptors and Their Coactivators on Nutrient and Energy Metabolism. Nutrients 2022; 14:nu14245378. [PMID: 36558537 PMCID: PMC9782515 DOI: 10.3390/nu14245378] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Genetic components may play an important role in the regulation of nutrient and energy metabolism. In the presence of specific genetic variants, metabolic dysregulation may occur, especially in relation to the processes of digestion, assimilation, and the physiological utilization of nutrients supplied to the body, as well as the regulation of various metabolic pathways and the balance of metabolic changes, which may consequently affect the effectiveness of applied reduction diets and weight loss after training. There are many well-documented studies showing that the presence of certain polymorphic variants in some genes can be associated with specific changes in nutrient and energy metabolism, and consequently, with more or less desirable effects of applied caloric reduction and/or exercise intervention. This systematic review focused on the role of genes encoding peroxisome proliferator-activated receptors (PPARs) and their coactivators in nutrient and energy metabolism. The literature review prepared showed that there is a link between the presence of specific alleles described at different polymorphic points in PPAR genes and various human body characteristics that are crucial for the efficacy of nutritional and/or exercise interventions. Genetic analysis can be a valuable element that complements the work of a dietitian or trainer, allowing for the planning of a personalized diet or training that makes the best use of the innate metabolic characteristics of the person who is the subject of their interventions.
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Affiliation(s)
- Agnieszka Maciejewska-Skrendo
- Faculty of Physical Culture, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland
- Institute of Physical Culture Sciences, University of Szczecin, 71-065 Szczecin, Poland
- Correspondence:
| | - Myosotis Massidda
- Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, Sport and Exercise Sciences Degree Courses, University of Cagliari, 72-09124 Cagliari, Italy
| | - Filippo Tocco
- Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, Sport and Exercise Sciences Degree Courses, University of Cagliari, 72-09124 Cagliari, Italy
| | - Katarzyna Leźnicka
- Faculty of Physical Culture, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland
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Song J, Li N, Hu R, Yu Y, Xu K, Ling H, Lu Q, Yang T, Wang T, Yin X. Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2022; 13:949990. [PMID: 36051387 PMCID: PMC9424689 DOI: 10.3389/fendo.2022.949990] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 07/22/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Exenatide is a GLP-1R agonist that often exhibits considerable interindividual variability in therapeutic efficacy. However, there is no evidence about the impact of genetic variants in the PPARD on the therapeutic efficacy of exenatide. This research was aimed to explore the influence of PPARD gene polymorphism on the therapeutic effect of exenatide, and to identify the potential mechanism futher. METHODS A total of 300 patients with T2DM and 200 control subjects were enrolled to identify PPARD rs2016520 and rs3777744 genotypes. A prospective clinical study was used to collect clinical indicators and peripheral blood of T2DM patients treated with exenatide monotherapy for 6 months. The SNaPshot method was used to identify PPARD rs2016520 and rs3777744 genotypes, and then we performed correlation analysis between PPARD gene variants and the efficacy of exenatide, and conducted multiple linear regression analysis of factors affecting the therapeutic effect of exenatide. HepG2 cells were incubated with exenatide in the absence or presence of a PPARδ agonist or the siPPARδ plasmid, after which the levels of GLP-1R and the ratio of glucose uptake were determined. RESULTS After 6 months exenatide monotherapy, we observed that homeostasis model assessment for insulin resistance (HOMA-IR) levels of the subjects with at least one C allele of the PPARD rs2016520 were significantly lower than those with the TT genotype, which suggested that the PPARD rs2016520 TT genotype conferred the poor exenatide response through a reduction of insulin resistance, as measured by HOMA-IR. The carriers of G alleles at rs3777744 exhibited higher levels of in waist to hip ratio (WHR), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and HOMA-IR compared to individuals with the AA genotype following 6 months of exenatide treatment, potentially accounting for the lower failure rate of exenatide therapy among the AA homozygotes. In an insulin resistant HepG2 cell model, the PPARδ agonists enhanced exenatide efficacy on insulin resistance, with the expression of GLP-1R being up-regulated markedly. CONCLUSION These data suggest that the PPARD rs2016520 and rs3777744 polymorphisms are associated with exenatide monotherapy efficacy, due to the pivotal role of PPARδ in regulating insulin resistance through affecting the expression of GLP-1R. This study was registered in the Chinese Clinical Trial Register (No. ChiCTR-CCC13003536).
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Affiliation(s)
- Jinfang Song
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Na Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ruonan Hu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yanan Yu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Ke Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Hongwei Ling
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Tao Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- Department of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- *Correspondence: Tao Wang, ; Xiaoxing Yin,
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
- *Correspondence: Tao Wang, ; Xiaoxing Yin,
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Huang Y, Sun X, Jiang H, Yu S, Robins C, Armstrong MJ, Li R, Mei Z, Shi X, Gerasimov ES, De Jager PL, Bennett DA, Wingo AP, Jin P, Wingo TS, Qin ZS. A machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer's disease. Nat Commun 2021; 12:4472. [PMID: 34294691 PMCID: PMC8298578 DOI: 10.1038/s41467-021-24710-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 06/28/2021] [Indexed: 12/21/2022] Open
Abstract
Alzheimer's disease (AD) is influenced by both genetic and environmental factors; thus, brain epigenomic alterations may provide insights into AD pathogenesis. Multiple array-based Epigenome-Wide Association Studies (EWASs) have identified robust brain methylation changes in AD; however, array-based assays only test about 2% of all CpG sites in the genome. Here, we develop EWASplus, a computational method that uses a supervised machine learning strategy to extend EWAS coverage to the entire genome. Application to six AD-related traits predicts hundreds of new significant brain CpGs associated with AD, some of which are further validated experimentally. EWASplus also performs well on data collected from independent cohorts and different brain regions. Genes found near top EWASplus loci are enriched for kinases and for genes with evidence for physical interactions with known AD genes. In this work, we show that EWASplus implicates additional epigenetic loci for AD that are not found using array-based AD EWASs.
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Affiliation(s)
- Yanting Huang
- Department of Computer Science, Emory University, Atlanta, GA, USA
| | - Xiaobo Sun
- Department of Mathematical and Statistical Finance, School of Statistics and Mathematics, Zhongnan University of Economics and Laws, Wuhan, Hubei, China.
| | - Huige Jiang
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Shaojun Yu
- Department of Computer Science, Emory University, Atlanta, GA, USA
| | - Chloe Robins
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Matthew J Armstrong
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Ronghua Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Zhen Mei
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Xiaochuan Shi
- Department of Statistics, University of Washington, Seattle, WA, USA
| | | | - Philip L De Jager
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Aliza P Wingo
- Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, USA
- Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Thomas S Wingo
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
| | - Zhaohui S Qin
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
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Carrillo-Venzor MA, Erives-Anchondo NR, Moreno-González JG, Moreno-Brito V, Licón-Trillo A, González-Rodríguez E, Hernández-Rodríguez PDC, Reza-López SA, Loera-Castañeda V, Leal-Berumen I. Pro12Ala PPAR-γ2 and +294T/C PPAR-δ Polymorphisms and Association with Metabolic Traits in Teenagers from Northern Mexico. Genes (Basel) 2020; 11:genes11070776. [PMID: 32664384 PMCID: PMC7397260 DOI: 10.3390/genes11070776] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/01/2020] [Accepted: 07/07/2020] [Indexed: 11/20/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) play roles in glucose and lipid metabolism regulation. Pro12Ala PPAR-γ2 and +294T/C PPAR-δ have been associated with dyslipidemia, hyperglycemia and high body mass index (BMI). We compared metabolic traits and determined associations with Pro12Ala PPAR-γ2 or +294T/C PPAR-δ polymorphism among teenagers from different ethnicity. Four hundred and twelve samples with previous biochemical and biometric measurements were used. Genomic DNA from peripheral blood was extracted and analyzed by end-point PCR for Pro12Ala PPAR-γ2. The +294T/C PPAR-δ PCR product was also digested with Bsl I. Two genotype groups were formed: major allele homozygous and minor allele carriers. Pro12Ala PPAR-γ2 G minor allele frequencies were: 10% in Mestizo-1, 19% in Mestizo-2, 23% in Tarahumara, 12% in Mennonite, and 17% in the total studied population. The +294T/C PPAR-δ C minor allele frequencies were: 18% in Mestizo-1, 20% in Mestizo-2, 6% in Tarahumara, 13% in Mennonite, and 12% in the total studied population. Teenagers with PPAR-γ2 G allele showed a greater risk for either high waist/height ratio or low high-density lipoprotein; and, also had lower total cholesterol. Whereas, PPAR-γ2 G allele showed lower overweight/obesity phenotype (BMI Z-score) frequency, PPAR-δ C allele was a risk factor for it. Metabolic traits were associated with both PPAR polymorphisms.
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Affiliation(s)
- Martín A. Carrillo-Venzor
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | - Nancy R. Erives-Anchondo
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | - Janette G. Moreno-González
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | - Verónica Moreno-Brito
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | - Angel Licón-Trillo
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | - Everardo González-Rodríguez
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | | | - Sandra A. Reza-López
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
| | | | - Irene Leal-Berumen
- Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua, Circuito Universitario, Campus II, Chihuahua 31109, Mexico; (M.A.C.-V.); (N.R.E.-A.); (J.G.M.-G.); (V.M.-B.); (A.L.T.); (E.G.-R.); (S.A.R.-L.)
- Correspondence:
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10
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Leońska-Duniec A, Cieszczyk P, Jastrzębski Z, Jażdżewska A, Lulińska-Kuklik E, Moska W, Ficek K, Niewczas M, Maciejewska-Skrendo A. The polymorphisms of the PPARD gene modify post-training body mass and biochemical parameter changes in women. PLoS One 2018; 13:e0202557. [PMID: 30157214 PMCID: PMC6114845 DOI: 10.1371/journal.pone.0202557] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 08/06/2018] [Indexed: 11/18/2022] Open
Abstract
In this study we examined the genotype distribution of the PPARD rs2267668, rs2016520, and rs1053049 alleles in a group of women, before and after the completion of a 12-week training program. There were two significant genotype × training interactions resulting in decreases of total cholesterol (Chol) through training in rs2267668 G allele carriers and significant increases of triglyceride (TGL) levels in rs2267668 AA homozygotes. Carriers of rs2016520 PPARD C allele exhibited a significant decrease in Chol through training with an accompanying decrease in TGL. There was also overrepresentation of PPARD rs1053049 TT homozygotes in the group with higher post-training TGL levels. Moreover (rs2267668/rs2016520/rs1053049) G/C/T haplotype displayed smaller post-training body mass decrease, suggesting that harboring this specific G/C/T haplotype is unfavorable for achieving the desired training-induced body mass changes. On the other hand, the G/C/C haplotype was significantly associated with post-training increase in fat free mass (FFM) and with lower levels of Chol as well as TGL as observed in the blood of the participants in response to applied training. This observation constitutes the second important finding of the study, implying that when specific training-induced biochemical changes are taken into account, some individuals may benefit from carrying the G/C/C haplotype.
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Affiliation(s)
- Agata Leońska-Duniec
- Faculty of Physical Culture and Health Promotion, Szczecin University, Szczecin, Poland
- Faculty of Physical Education, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Pawel Cieszczyk
- Faculty of Physical Education, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Zbigniew Jastrzębski
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Aleksandra Jażdżewska
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Ewelina Lulińska-Kuklik
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Waldemar Moska
- Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Krzysztof Ficek
- Faculty of Physiotherapy, The Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland
| | - Marta Niewczas
- University of Rzeszów, Faculty of Physical Education, Rzeszów, Poland
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11
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Kim M, Kim M, Yoo HJ, Sun Y, Lee SH, Lee JH. PPARD rs7770619 polymorphism in a Korean population: Association with plasma malondialdehyde and impaired fasting glucose or newly diagnosed type 2 diabetes. Diab Vasc Dis Res 2018; 15:360-363. [PMID: 29776318 DOI: 10.1177/1479164118776414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Both the peroxisome proliferator-activated receptor delta gene ( PPARD) and malondialdehyde plasma concentrations may play a role in impaired glucose metabolism. The aim of this work was to determine whether PPARD is a candidate gene for impaired fasting glucose or type 2 diabetes and whether a particular genetic variant shows association with plasma malondialdehyde levels. Among the 10 single-nucleotide polymorphisms that were most strongly associated with malondialdehyde, the rs7770619 polymorphism in PPARD was analysed in 1798 subjects with normal fasting glucose, impaired fasting glucose and newly diagnosed type 2 diabetes. Our data demonstrate that the CT genotype of the rs7770619 is associated with a lower risk of impaired fasting glucose or type 2 diabetes together with lower plasma levels of malondialdehyde in both groups ( p < 0.05). Glucose levels and the rs7770619 are significantly associated in individuals with normal fasting glucose, and a trend towards an association between glucose levels and rs7770619 is also observed in individuals with impaired fasting glucose or type 2 diabetes. In conclusion, PPARD rs7770619 is a novel candidate variant for impaired fasting glucose and type 2 diabetes and shows association with malondialdehyde levels. Future work is required to understand the mechanisms for these associations and the clinical implications of our findings.
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Affiliation(s)
- Minjoo Kim
- 1 Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
| | - Minkyung Kim
- 1 Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
| | - Hye Jin Yoo
- 2 Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Yao Sun
- 3 Department of Science for Aging, Graduate School of Yonsei University, Seoul, Korea
| | - Sang-Hyun Lee
- 4 Department of Family Practice, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
| | - Jong Ho Lee
- 1 Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, Korea
- 2 Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
- 5 National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
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Raj R, Bhatti JS, Bhadada SK, Ramteke PW. Association of polymorphisms of peroxisome proliferator activated receptors in early and late onset of type 2 diabetes mellitus. Diabetes Metab Syndr 2017; 11 Suppl 1:S287-S293. [PMID: 28292576 DOI: 10.1016/j.dsx.2017.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/03/2017] [Indexed: 12/06/2022]
Abstract
OBJECTIVE Genetic variation of disease susceptible genes is different in different ethnic groups and there is an evidence of association of polymorphisms of Peroxisome Proliferator Activated Receptors (PPARs) in Type 2 Diabetes Mellitus (T2DM). This research analyses the association of PPARs in early and late onset of T2DM in North Indian Population (NIP). METHODS Total of 703 subjects were recruited from north of India and subjects were further divided into subjects of early onset (less than 25 years of onset, 26 T2DM and 26 controls) and late onset (more than 25 years of onset, 326 T2DM and 325 controls). RESULT The onset of T2DM begins from 15 years and continues further to maximum T2DM subjects to the age of 50 (76% of T2DM). High BMI and WHR, high blood pressure leading to early onset of hypertension, early mortality due to T2DM (7% of T2DM is above 75 years and 3% of T2DM has 20 years duration of onset) and high hyperglycemic NIP were the few outcomes of this research. CONCLUSION There is a strong association of PPAR γ, PPAR α and PPAR δ genes on the susceptibility of T2DM in late onset but not with the early onset of T2DM subjects in North Indian Population: Dual association of PPAR γ was observed with its genotype G/G (Ala/Ala) favoring protection against T2DM and genotype C/C (Pro/Pro) favoring susceptibility to T2DM. Association of intron7 polymorphism of PPAR α and +T294C polymorphism of PPAR δ on the susceptibility to T2DM requires further analysis.
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Affiliation(s)
- Resal Raj
- Department of Computational Biology & Bioinformatics, Sam Higginbottom Institute of Agriculture, Technology and Sciences, Allahabad, UP, India.
| | - Jasvinder Singh Bhatti
- Department of Biotechnology & Bioinformatics, SGGS College, Sector L26 Chandigarh, India
| | | | - Pramod W Ramteke
- Department of Biological Sciences, Sam Higginbottom Institute of Agriculture, Technology and Sciences, Deemed to be University, Allahabad, India
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13
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Beyaz S, Yilmaz ÖH. Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway. Clin Cancer Res 2016; 22:5636-5641. [PMID: 27702819 DOI: 10.1158/1078-0432.ccr-16-0775] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/06/2016] [Accepted: 09/07/2016] [Indexed: 12/30/2022]
Abstract
Peroxisome proliferator-activated receptor delta (PPAR-δ) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR-δ during tumorigenesis is not well understood. Recent data suggest that PPAR-δ may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR-δ program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-δ pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR-δ agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-δ mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. Clin Cancer Res; 22(23); 5636-41. ©2016 AACR.
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Affiliation(s)
- Semir Beyaz
- The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts
| | - Ömer H Yilmaz
- The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts. .,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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14
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Kasim NB, Huri HZ, Vethakkan SR, Ibrahim L, Abdullah BM. Genetic polymorphisms associated with overweight and obesity in uncontrolled Type 2 diabetes mellitus. Biomark Med 2016; 10:403-15. [DOI: 10.2217/bmm-2015-0037] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Generally, obese and overweight individuals display higher free fatty acid levels, which stimulate insulin resistance. The combination of overweight or obesity with insulin resistance can trigger Type 2 diabetes mellitus (T2DM) and are primary contributing factors to the development of uncontrolled T2DM. Genetic polymorphisms also play an important role as they can impact a population's susceptibility to becoming overweight or obese and developing related chronic complications, such as uncontrolled T2DM. This review specifically examines the genetic polymorphisms associated with overweight and obesity in patients with uncontrolled T2DM. Particularly, gene polymorphisms in ADIPOQ (rs1501299 and rs17300539), LepR (rs1137101 and rs1045895), IRS2 (rs1805092), GRB14 (rs10195252 and rs3923113) and PPARG (rs1801282) have been associated with overweight and obesity in uncontrolled T2DM.
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Affiliation(s)
- Nor Bahirah Kasim
- Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Hasniza Zaman Huri
- Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Clinical Investigation Centre, Faculty of Medicine, 13th Floor Main Tower, University Malaya Medical Centre, 59100 Lembah Pantai Kuala Lumpur, Malaysia
| | | | - Luqman Ibrahim
- Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Bashar Mudhaffar Abdullah
- Clinical Investigation Centre, Faculty of Medicine, 13th Floor Main Tower, University Malaya Medical Centre, 59100 Lembah Pantai Kuala Lumpur, Malaysia
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15
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Ding XY, Yuan HZ, Gu R, Gao YF, Liu XG, Gao Y. The Association of Peroxisome Proliferator-Activated Receptor δ and Additional Gene-Gene Interaction with C-Reactive Protein in Chinese Population. Int J Endocrinol 2016; 2016:8597085. [PMID: 26884762 PMCID: PMC4738690 DOI: 10.1155/2016/8597085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/08/2015] [Indexed: 11/17/2022] Open
Abstract
Aims. To examine the association between 4 single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors δ (PPARδ) polymorphisms and C-reactive protein (CRP) level and additional gene-gene interaction. Methods. Line regression analysis was performed to verify polymorphism association between SNP and CRP levels. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the interaction. Results. A total of 1028 subjects (538 men, 490 women) were selected. The carriers of the C allele (TC or CC) of rs2016520 were associated with a significant decreased level of CRP, regression coefficients was -0.338, and standard error was 0.104 (p = 0.001). The carriers of the G allele (CG or GG) of rs9794 were also significantly associated with decreased level of CRP, regression coefficients was -0.219, and standard error was 0.114 (p = 0.012). We also found a potential gene-gene interaction between rs2016520 and rs9794. Subjects with rs2016520-TC or CC, rs9794-CG or GG genotypes have lowest CRP level, difference (95% CI) = -0.50 (-0.69 to -0.21) (p < 0.001), compared to subjects with rs2016520-TT and rs9794-CC genotypes. Conclusions. rs2016520 and rs9794 minor allele of PPARδ and combined effect between the two SNP were associated with decreased CRP level.
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Affiliation(s)
- Xiao-Ying Ding
- Department of Anesthesia, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Hao-Zheng Yuan
- Department of Anesthesia, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Ru Gu
- Department of Anesthesia, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Yan-Feng Gao
- Department of Anesthesia, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xiao-Gang Liu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
- *Xiao-Gang Liu: and
| | - Ya Gao
- Department of Pediatric Surgery, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
- *Ya Gao:
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Is there a relationship between PPARD T294C/PPARGC1A Gly482Ser variations and physical endurance performance in the Korean population? Genes Genomics 2015. [DOI: 10.1007/s13258-015-0380-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Chia PP, Fan SH, Say YH. Screening of Peroxisome Proliferator-Activated Receptors (PPARs) α, γ and α Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-Ethnic Malaysian Population. Ethn Dis 2015; 25:383-90. [PMID: 26673968 DOI: 10.18865/ed.25.4.383] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE This study aimed to investigate the association of peroxisome proliferator-activated receptor (PPAR) genes PPARα L162V, PPARγ2 C161T and PPARδ T294C single nucleotide polymorphisms (SNPs) with obesity and metabolic syndrome (Met-S) in a multi-ethnic population in Kampar, Malaysia. METHODS Socio-demographic data, anthropometric and biochemical measurements (plasma lipid profile, adiponectin and interleukin-6 [IL-6] levels) were taken from 307 participants (124 males; 180 obese; 249 Met-S; 97 Malays, 85 ethnic Chinese, 55 ethnic Indians). RESULTS The overall minor allele frequencies were .08, .22 and .30 for PPAR α L162V, γ C161T, δ T294C, respectively. All SNPs were not associated with obesity, Met-S and obesity with/without Met-S by χ(2) analysis, ethnicity-stratified and logistic regression analyses. Nevertheless, participants with V162 allele of PPARα had significantly higher IL-6, while those with T161 allele of PPARγ2 had significantly lower HOMA-IR. CONCLUSIONS All PPAR SNPs were not associated with obesity and Met-S in the suburban population of Kampar, Malaysia, where only PPARα V162 and PPARγ2 T161 alleles were associated with plasma IL-6 and HOMA-IR, respectively.
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Affiliation(s)
- Phee-Phee Chia
- 1. Department of Science and Engineering, Centre for Foundation Studies, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
| | - Sook-Ha Fan
- 2. Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
| | - Yee-How Say
- 2. Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Perak Campus, Kampar, Perak, Malaysia
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Luo W, Chen F, Guo Z, Wu M, Zhou Z, Yao X. A population association study of PPAR δ gene rs2016520 and rs9794 polymorphisms and haplotypes with body mass index and waist circumference in a Chinese population. Ann Hum Biol 2015; 43:67-72. [PMID: 26073637 DOI: 10.3109/03014460.2015.1023847] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Peroxisome proliferator-activated receptor (PPAR) gene plays an important role in obesity and PPAR δ protein is a potent inhibitor; however, few previous studies have focused on this gene. AIM To investigate the association of haplotypes of PPAR δ gene rs2016520 and rs9794 with abnormal weight (BMI ≥ 24 kg/m(2)) and abdominal obesity (WC ≥ 90 cm for males and ≥ 80 cm for females) in a Chinese Han population. SUBJECTS AND METHODS In total, 820 subjects (270 men, 550 women) were randomly selected from the PMMJS cohort population and no individuals were related. rs2016520 and rs9794 were detected by TaqMan fluorescence probe. Hardy-Weinberg equilibrium (HWE) was used to detect genotype typing errors by Fisher's exact test. Linkage disequilibrium (LD) between polymorphisms was estimated by using SHEsis. Two PPAR δ SNPs (rs2016520 and rs9794) were analysed by using the logistic regression model. RESULTS After adjustment for covariates, the haplotype containing the rs1026520-C and rs9794-C alleles was associated with a statistically significant decreased risk of obesity (OR = 0.64; 95% CI = 0.48-0.84, p = 0.0015). Coincidentally, the haplotype containing the rs1026520-C and rs9794-C alleles was also associated with a statistically decreased risk of abdominal obesity after covariate adjustment (OR = 0.59, 95% CI = 0.45-0.77, p < 0.001). CONCLUSION C-C haplotype, constructed from rs2016520 and rs9794 alleles, showed a significant protective effect for both abnormal weight and abdominal obesity.
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Affiliation(s)
- Wenshu Luo
- a Changzhou Center for Disease Control and Prevention , Changzhou , Jiangsu , PR China .,b Suzhou Health College , Suzhou , Jiangsu , PR China
| | - Fengmei Chen
- b Suzhou Health College , Suzhou , Jiangsu , PR China
| | - Zhirong Guo
- c Department of Public Health , Soochow University , Suzhou , Jiangsu , PR China
| | - Ming Wu
- d Center for Disease Control of Jiangsu Province , Nanjing , Jiangsu , PR China , and
| | - Zhengyuan Zhou
- e Center for Disease Control of Changshu , Suzhou , Jiangsu , PR China
| | - Xingjuan Yao
- a Changzhou Center for Disease Control and Prevention , Changzhou , Jiangsu , PR China
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Dong C, Zhou H, Shen C, Yu LG, Ding Y, Zhang YH, Guo ZR. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome. World J Diabetes 2015; 6:654-661. [PMID: 25987964 PMCID: PMC4434087 DOI: 10.4239/wjd.v6.i4.654] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/27/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.
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Giordano Attianese GMP, Desvergne B. Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function. NUCLEAR RECEPTOR SIGNALING 2015; 13:e001. [PMID: 25945080 PMCID: PMC4419664 DOI: 10.1621/nrs.13001] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/09/2015] [Indexed: 12/13/2022]
Abstract
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding.
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Luo CY, Liu CW, Ge L, Pang GF, Yang M, Hu CY, Lv ZP, Chen NY, Li HY, Wu HY, Wang YY, Yin RX, Pan SL, Peng JH. PPARD +294C overrepresentation in general and long-lived population in China Bama longevity area and unique relationships between PPARD +294T/C polymorphism and serum lipid profiles. Lipids Health Dis 2015; 14:17. [PMID: 25873088 PMCID: PMC4356147 DOI: 10.1186/s12944-015-0016-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 02/23/2015] [Indexed: 11/18/2022] Open
Abstract
Background The +294T/C polymorphism in the peroxisome proliferator-activated receptor delta (PPARD) gene is associated with hyperlipidemia in several younger populations, but results are still inconsistence across ethnic groups and its possible impact on the lipid profiles of long-lived individuals remains unexploited. Here, we aimed to evaluate the possible correlation between PPARD +294T/C and serum lipid levels in a long-lived population in Bama, a region known for longevity situated in Guangxi, China. Methods Genotyping of PPARD +294T/C polymorphism was conducted in 505 long-lived inhabitants (aged 90 and above, long-lived group, LG) and 468 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Results No difference in allelic and genotypic frequencies was found between the two groups (P > 0.05). However, C-allele and C-genotype (TC and CC) were significantly more frequent in the females of non-LG than were LG after sex stratification. CC carriers exhibited higher LDL-C level in LG (P < 0.05) but lower TC, TG and LDL-C in non-LG (P < 0.05 for each) than TT carriers; C allele carriers (TC/CC) in LG exhibited higher TC, TG, and LDL-C levels as compared with the same genotype and the same lipid parameter in non-LG (P < 0.05 for each). LDL-C in LG was correlated with genotypes while TC, TG, and LDL-C in non-LG were correlated with genotypes (P < 0.05-0.001). Conclusion Our results suggest that there were different impact patterns of PPARD +294T/C polymorphism on lipid profiles between long-lived cohort and average population in Bama area and this may be one of the genetic bases of its longevity.
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Shim U, Kim HN, Sung YA, Kim HL. Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts. Genomics Inform 2014; 12:195-202. [PMID: 25705158 PMCID: PMC4330254 DOI: 10.5808/gi.2014.12.4.195] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/05/2014] [Accepted: 09/12/2014] [Indexed: 01/07/2023] Open
Abstract
Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 ± 8.9 years; body mass index, 24.6 ± 3.2 kg/m(2)). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 × 10(-6)), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 × 10(-7), Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS.
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Affiliation(s)
- Unjin Shim
- Department of Internal Medicine, Seoul Seonam Hospital, Ewha Womans University Medical Center, Seoul 158-070, Korea
| | - Han-Na Kim
- Department of Biochemistry, Ewha Womans University School of Medicine, Seoul 158-710, Korea
| | - Yeon-Ah Sung
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Korea
| | - Hyung-Lae Kim
- Department of Biochemistry, Ewha Womans University School of Medicine, Seoul 158-710, Korea
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Song JF, Wang T, Zhu J, Zhou XY, Lu Q, Guo H, Zhang F, Wang Y, Li W, Wang DD, Cui YW, Lv DM, Yin XX. PPARDrs2016520 polymorphism affects repaglinide response in Chinese Han patients with type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2014; 42:27-32. [PMID: 25311380 DOI: 10.1111/1440-1681.12314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 09/19/2014] [Accepted: 09/23/2014] [Indexed: 11/27/2022]
Affiliation(s)
- Jin-Fang Song
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
- Department of Pharmacy; Wuxi Third People's Hospital; Wuxi China
| | - Tao Wang
- Department of Pharmacy; the Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Jing Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
| | - Xue-Yan Zhou
- Department of Clinical Pharmacology; Xuzhou Medical College; Xuzhou China
| | - Qian Lu
- Department of Clinical Pharmacology; Xuzhou Medical College; Xuzhou China
| | - Hao Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
| | - Fan Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
| | - Yan Wang
- Department of Pharmacy; the Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Wei Li
- Depatment of Endocrinology; the Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Dan-Dan Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
| | - Ya-Wen Cui
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
| | - Dong-Mei Lv
- Department of Pharmacy; the Affiliated Hospital of Xuzhou Medical College; Xuzhou China
| | - Xiao-Xing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy; Xuzhou Medical College; Xuzhou China
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Villegas R, Williams SM, Gao YT, Long J, Shi J, Cai H, Li H, Chen CC, Tai ES, Hu F, Cai Q, Zheng W, Shu XO. Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes. Ann Hum Genet 2014; 78:23-32. [PMID: 24359475 DOI: 10.1111/ahg.12044] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 09/01/2013] [Indexed: 12/30/2022]
Abstract
We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the PPAR gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta-analysis or (2) P < 10(-3) in the meta-analysis alone and (3) minor allele frequency ≥ 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77-0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.
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Affiliation(s)
- Raquel Villegas
- Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Park SK, Park CS, Lee HS, Park KS, Park BL, Cheong HS, Shin HD. Functional polymorphism in aldehyde dehydrogenase-2 gene associated with risk of tuberculosis. BMC MEDICAL GENETICS 2014; 15:40. [PMID: 24690209 PMCID: PMC3975138 DOI: 10.1186/1471-2350-15-40] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 03/27/2014] [Indexed: 11/29/2022]
Abstract
Background The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde. We investigated possible involvement of these functional polymorphisms in other common complex-trait diseases. Methods The genetic effects of these two polymorphisms on hepatitis, asthma, type-2 diabetes mellitus (T2DM), and tuberculosis (TB) were examined in a Korean population. Results We demonstrated that the well-known functional polymorphism of a primary alcohol-metabolizing enzyme (ALDH2 Glu487Lys) has a strong genetic association with the risk of TB. The frequency of the minor allele (ALDH2*487Lys) was found to be much lower in TB patients (freq. = 0.099/n = 477) than among controls (freq. = 0.162/n = 796) (P = 0.00001, OR (95% confidential interval) = 0.57 (0.45-0.74)). Our data may indicate that TB was once an endemic disease, which exerted selection pressure for higher frequencies of ALDH2*487Lys in Asian populations. In addition, the calculated attributable fraction (AF) indicates that 39.5% of TB patients can attribute their disease to the detrimental effects of ALDH2Glu487Glu. Conclusion Our results suggest that this polymorphism is one of the genetic components of TB, at least in the Korean population.
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Affiliation(s)
| | | | | | | | | | | | - Hyoung Doo Shin
- Department of Genetic Epidemiology, SNP Genetics, Inc,, 1 Shinsu-dong, Mapo-gu, Seoul 121-742, Republic of Korea.
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Cha YS, Park Y, Lee M, Chae SW, Park K, Kim Y, Lee HS. Doenjang, a Korean fermented soy food, exerts antiobesity and antioxidative activities in overweight subjects with the PPAR-γ2 C1431T polymorphism: 12-week, double-blind randomized clinical trial. J Med Food 2014; 17:119-27. [PMID: 24456362 DOI: 10.1089/jmf.2013.2877] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
We examined the antiobesity and antioxidant effects of supplementation with doenjang, a fermented soybean paste, in overweight Koreans with the PPAR-γ2 C1431T polymorphism. Sixty overweight subjects were randomly assigned to consume either 9.8 g/day of doenjang or placebo for 12 weeks. Before and after the intervention, anthropometric and metabolic parameters, along with abdominal fat distribution and PPAR-γ2 polymorphisms, were measured. Fifty-one subjects completed the study, doenjang (n=26) and placebo (n=25) groups. Relative frequencies of the PPAR-γ2 genotypes CC, TC, and TT were 70% (n=41), 25.9% (15), and 3.4% (2), whereas those of the PPAR-γ2 alleles C and T were 81.6% and 18.4%. Visceral fat area (VFA) was significantly decreased by doenjang supplementation in subjects with a mutant T allele of PPAR-γ2 compared to those with a C allele after adjusting for age, sex, and body mass index. Plasma free fatty acid, insulin, and homeostatic model assessment insulin resistance (HOMA-IR) levels were also significantly increased in the doenjang group. Doenjang pills significantly activated radical clearance capacity (ORAC and DNA tail length) in subjects with the C allele. The catalase (CAT) activity was increased twofold in the doenjang-treated group with the C allele, but this phenomenon was reversed in those with the T allele. Doenjang-treated subjects tended to have low dietary carbohydrate and sodium intakes compared with those given placebo. We found that doenjang supplementation decreased visceral fat accumulation and aging most effectively in subjects with PPAR-γ polymorphisms. This study suggests that doenjang has antiobesity and antioxidative effects in overweight individuals with mutant alleles of PPAR-γ2.
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Affiliation(s)
- Youn-Soo Cha
- 1 Department of Food Science and Human Nutrition, Obesity Research Center, Chonbuk National University , Jeonju, Republic of Korea
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Polymorphisms in PPAR Genes (PPARD, PPARG, and PPARGC1A) and the Risk of Chronic Kidney Disease in Japanese: Cross-Sectional Data from the J-MICC Study. PPAR Res 2013; 2013:980471. [PMID: 24288525 PMCID: PMC3830885 DOI: 10.1155/2013/980471] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 08/28/2013] [Accepted: 09/09/2013] [Indexed: 12/27/2022] Open
Abstract
Chronic kidney disease (CKD) is well known as a strong risk factor for both end stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in the PPAR genes (PPARD, PPARG, and PPARGC1A) with the risk of CKD in Japanese, we examined this association among the Japanese subjects using the cross-sectional data of J-MICC (Japan Multi-Institutional Collaborative Cohort) Study. The subjects for this analysis were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants; genotyping was conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (defined as eGFR < 60 ml/min/1.73 m2). Participants with CKD accounted for 17.3% of the study population. When those with PPARD T-842C T/T were defined as reference, those with PPARD T-842C T/C and C/C demonstrated the OR for CKD of 1.26 (95%CI 1.04–1.53) and 1.31 (95%CI 0.83–2.06), respectively. There were no significant associations between the polymorphisms in other PPAR genes and the risk of CKD. The present study found a significantly increased risk of CKD in those with the C allele of PPARD T-842C, which may suggest the possibility of personalized risk estimation of this life-limiting disease in the near future.
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Yao C, Spurlock D, Armentano L, Page C, VandeHaar M, Bickhart D, Weigel K. Random Forests approach for identifying additive and epistatic single nucleotide polymorphisms associated with residual feed intake in dairy cattle. J Dairy Sci 2013; 96:6716-29. [DOI: 10.3168/jds.2012-6237] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 06/20/2013] [Indexed: 01/23/2023]
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Ehrenborg E, Skogsberg J. Peroxisome proliferator-activated receptor delta and cardiovascular disease. Atherosclerosis 2013; 231:95-106. [PMID: 24125418 DOI: 10.1016/j.atherosclerosis.2013.08.027] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 08/16/2013] [Accepted: 08/27/2013] [Indexed: 12/20/2022]
Abstract
Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD). Specific human PPARD gene variants show no clear association with CVD but interactions between variants and lifestyle factors might influence disease risk. During recent years, development of specific and potent PPARD agonists has also made it possible to study the effects of PPARD activation in humans. PPARD agonists seem to exert beneficial effects on dyslipidemia and insulin-resistant syndromes but safety issues have been raised due to the role that PPARD plays in cell proliferation. Thus, large long term outcome as well as detailed safety and tolerability studies are needed to evaluate whether PPARD agonists could be used to treat CVD in humans.
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Affiliation(s)
- Ewa Ehrenborg
- Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
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Luo W, Guo Z, Wu M, Hao C, Hu X, Zhou Z, Zhou Z, Yao X, Zhang L, Liu J. Association of peroxisome proliferator-activated receptor α/δ/γ with obesity, and gene-gene interaction, in the Chinese Han population. J Epidemiol 2013; 23:187-94. [PMID: 23545576 PMCID: PMC3700259 DOI: 10.2188/jea.je20120110] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARs) with obesity and the additional role of gene-gene interaction. METHODS Participants were recruited within the framework of the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort population survey of an urban community in China. In total, 820 subjects (513 nonobese adults, 307 obese adults) were randomly selected, and no individuals were consanguineous. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped and analyzed. RESULTS After covariate adjustment, minor alleles of rs2016520 in PPARδ and rs10865170 in PPARγ were associated with lower BMI (P < 0.01 for all). Generalized multifactor dimensionality reduction analysis showed significant gene-gene interaction among rs2016520, rs9794, and rs10865170 in 3-dimensional models (P = 0.0010); prediction accuracy was 0.6011 and cross-validation consistency was 9/10. It also showed significant gene-gene interaction between rs2016520 and rs10865170 in all 2-dimensional models (P = 0.0010); prediction accuracy was 0.6072 and cross-validation consistency was 9/10. CONCLUSIONS rs2016520 and rs10865170 were associated with lower obesity risk. In addition, interaction was identified among rs2016520, rs9794, and rs10865170 in obesity.
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Affiliation(s)
- Wenshu Luo
- Changzhou Center for Disease Control and Prevention, Changzhou, Jiangsu, China
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Effect of genetic polymorphism +294T/C in peroxisome proliferator-activated receptor delta on the risk of ischemic stroke in a Tunisian population. J Mol Neurosci 2013; 50:360-7. [PMID: 23512374 DOI: 10.1007/s12031-013-9997-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Accepted: 03/05/2013] [Indexed: 12/14/2022]
Abstract
PPARδ +294T/C polymorphism was investigated in diabetics, in normolipidemic healthy controls, in dyslipidemic and nondyslipidemic coronary artery disease patients but never in ischemic stroke patients. The aim of this study was to explore, for the first time, the relationship between the genetic polymorphism of PPARδ and the risk of ischemic stroke among patients with diabetes. The study group consisted of 196 patients with ischemic stroke and 192 controls. Plasma concentrations of total cholesterol, triglycerides, low-, and high-density lipoprotein did not differ significantly between subjects carrying the TT genotype and those carrying the CC/TC genotype in both ischemic stroke patients (with or without diabetes) and control groups. The +294C allele (CC + CT genotypes) as compared with TT genotypes was found to be higher in total ischemic stroke patients than in controls. On the other hand, no interaction between diabetes and PPAR +294T/C polymorphism on the risk of ischemic stroke was found (p = 0.089). The PPARδ +294T/C polymorphism was associated with the risk of ischemic stroke in Tunisian subjects. This polymorphism has no influence on plasma lipoprotein concentrations and body mass index either in healthy subjects or in ischemic stroke patients with or without diabetes both in males and females.
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Gene-gene interaction between PPARδ and PPARγ is associated with abdominal obesity in a Chinese population. J Genet Genomics 2012; 39:625-31. [PMID: 23273766 DOI: 10.1016/j.jgg.2012.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/31/2012] [Accepted: 08/16/2012] [Indexed: 10/27/2022]
Abstract
The peroxisome proliferator-activated receptors (PPARs) -α, -δ/β and -γ are the ligand-activated transcription factors that function as the master regulators of glucose, fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation, inflammation, and atherosclerosis. The objective of the current study was to examine the main and interactive effect of seven single nucleotide polymorphisms (SNPs) of PPARδ/γ in contribution to abdominal obesity. A total of 820 subjects were randomly selected and no individuals were related. The selected SNPs in PPARδ (rs2016520 and rs9794) and PPARγ (rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped. Mean difference and 95% confident interval were calculated. Interactions were explored by the method of generalized multifactor dimensionality reduction. After adjustment for gender, age, and smoking status, it was found that the carriers of the C allele (TC + CC) of rs2016520 were associated with a decreased risk of abdominal obesity compared to the carriers of the TT genotype (mean difference = -2.63, 95% CI = -3.61--1.64, P < 0.0001). A significant two-locus model (P = 0.0107) involving rs2016520 and rs10865710 and a significant three-locus model (P = 0.0107) involving rs2016520, rs9794, and rs1805192 were observed. Overall, the three-locus model had the highest level of testing accuracy (59.85%) and showed a better cross-validation consistency (9/10) than two-locus model. Therefore, for abdominal obesity defined by waist circumference, we chose the three-locus model as the best interaction model. In conclusion, the C allele in rs2016520 was significantly associated with a lower abdominal obesity. Moreover, an interaction among rs2016520, rs1805192, and rs9794 on incident abdominal obesity could be demonstrated.
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Pérusse L, Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Snyder EE, Bouchard C. The Human Obesity Gene Map: The 2004 Update. ACTA ACUST UNITED AC 2012; 13:381-490. [PMID: 15833932 DOI: 10.1038/oby.2005.50] [Citation(s) in RCA: 175] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single-gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity-related phenotypes from 50 genome-wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http://obesitygene.pbrc.edu.
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Affiliation(s)
- Louis Pérusse
- Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Québec, Canada
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Lu L, Wu Y, Qi Q, Liu C, Gan W, Zhu J, Li H, Lin X. Associations of type 2 diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese. PLoS One 2012; 7:e34895. [PMID: 22509365 PMCID: PMC3324546 DOI: 10.1371/journal.pone.0034895] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 03/10/2012] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Previous studies have identified that variants in peroxisome proliferator-activated receptor PPAR-δ (PPARD), a target gene of vitamin D, were significantly associated with fasting glucose and insulin sensitivity in European populations. This current study sought to determine (1) whether the genetic associations of PPARD variants with type 2 diabetes and its related traits could be replicated in Chinese Han population, and (2) whether the associations would be modified by the effect of vitamin D status. METHODS AND FINDINGS We genotyped 9 tag single nucleotide polymorphisms (SNPs) that cover the gene of PPARD (rs2267664, rs6902123, rs3798343, rs2267665, rs2267668, rs2016520, rs2299869, rs1053049, and rs9658056) and tested their associations with type 2 diabetes risk and its related traits, including fasting glucose, insulin and HbA1c in 3,210 Chinese Hans. Among the 9 PPARD tag SNPs, rs6902123 was significantly associated with risk of type 2 diabetes (odds ratio 1.75 [95%CI 1.22-2.53]; P = 0.0025) and combined type 2 diabetes and impaired fasting glucose (IFG) (odds ratio 1.47 [95%CI 1.12-1.92]; P = 0.0054). The minor C allele of rs6902123 was associated with increased levels of fasting glucose (P = 0.0316) and HbA1c (P = 0.0180). In addition, we observed that vitamin D modified the effect of rs6902123 on HbA1c (P for interaction = 0.0347). CONCLUSIONS/SIGNIFICANCE Our findings demonstrate that common variants in PPARD contribute to the risk of type 2 diabetes in Chinese Hans, and provided suggestive evidence of interaction between 25(OH)D levels and PPARD-rs6902123 on HbA1c.
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Affiliation(s)
| | | | | | | | | | | | - Huaixing Li
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China
- * E-mail: (HL); (XL)
| | - Xu Lin
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China
- * E-mail: (HL); (XL)
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Villegas R, Williams S, Gao Y, Cai Q, Li H, Elasy T, Cai H, Edwards T, Xiang YB, Zheng W, Long J, Ou Shu X. Peroxisome proliferator-activated receptor delta (PPARD) genetic variation and type 2 diabetes in middle-aged Chinese women. Ann Hum Genet 2011; 75:621-9. [PMID: 21834910 DOI: 10.1111/j.1469-1809.2011.00669.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Animal studies have shown that the peroxime proliferator-activated receptor delta (PPARD) gene regulates glucose metabolism and insulin sensitivity. Genetic variation in the PPARD gene might affect physical endurance and has been associated with obesity. We investigated the independent and modifying effect of variants in the PPARD gene with exercise participation and body mass index (BMI) on type 2 diabetes (T2D), using data from a genome-wide association study (GWAS) of middle-aged women living in Shanghai, China, with 1019 T2D cases and 1709 controls. The genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. Imputation was used to determine missing genotypes. Participation in exercise was assessed by a questionnaire. Anthropometric variables were measured by trained interviewers. The association between polymorphisms and T2D was assessed by logistic regression analyses. The combined effects of polymorphisms in the PPARD gene with exercise participation and BMI on T2D risk was assessed by conducting stratified analysis with exercise participation and BMI categories. No significant associations between PPARD and T2D were found in either genotyped or imputed SNPs and no effect modification between exercise participation and PPARD genetic variation was found, suggesting that PPARD is not a risk factor for T2D in this population.
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Affiliation(s)
- Raquel Villegas
- Vanderbilt Epidemiology Center, Department of Medicine, Nashville, TN 37203-1738, USA.
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Vacca M, Degirolamo C, Mariani-Costantini R, Palasciano G, Moschetta A. Lipid-sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2011; 3:562-87. [PMID: 21755605 DOI: 10.1002/wsbm.137] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metabolic syndrome (MS) is a cluster of different diseases, namely central obesity, hypertension, hyperglycemia, and dyslipidemia, together with a pro-thrombotic and pro-inflammatory state. These metabolic abnormalities are often associated with an increased risk for cardiovascular disease (CVD) and cancer. Dietary and lifestyle modifications are currently believed more effective than pharmacological therapies in the management of MS patients. Nevertheless, the relatively low grade of compliance of patients to these recommendations, as well as the failure of current therapies, highlights the need for the discovery of new pharmacological and nutraceutic approaches. A deeper knowledge of the patho-physiological events that initiate and support the MS is mandatory. Lipid-sensing nuclear receptors (NRs) are the master transcriptional regulators of lipid and carbohydrate metabolism and inflammatory responses, thus standing as suitable targets. This review focuses on the physiological relevance of the NRs (peroxisome proliferator-activated receptors, liver X receptors, and farnesoid X receptor) in the control of whole-body homeostasis, with a special emphasis on lipid and glucose metabolism, and on the relationships between metabolic unbalances, systemic inflammation, and the onset of CVD. Future perspectives and possible clinical applications are also presented.
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Affiliation(s)
- Michele Vacca
- Clinica Medica Augusto Murri, Aldo Moro University of Bari, and Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy
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Abstract
Type 2 diabetes mellitus (T2DM) is caused by complex interplay between multiple genetic and environmental factors. The three major approaches used to identify the genetic susceptibility include candidate gene approach, familial linkage analysis and genome- wide association analysis. Recent advance in genome-wide association studies have greatly improved our understanding of the pathophysiology of T2DM. As of the end of 2010, there are more than 40 confirmed T2DM-associated genetic loci. Most of the T2DM susceptibility genes were implicated in decreased β-cell function. However, these genetic variations have a modest effect and their combination only explains less than 10% of the T2DM heritability. With the advent of the next-generation sequencing technology, we will soon identify rare variants of larger effect as well as causal variants. These advances in understanding the genetics of T2DM will lead to the development of new therapeutic and preventive strategies and individualized medicine.
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Affiliation(s)
- Kyong Soo Park
- Department of Internal Medicine and Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Korea
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Takiguchi E, Fukano C, Kimura Y, Tanaka M, Tanida K, Kaji H. Variation in the 5'-flanking region of the neuropeptide Y2 receptor gene and metabolic parameters. Metabolism 2010; 59:1591-6. [PMID: 20359722 DOI: 10.1016/j.metabol.2010.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Revised: 02/03/2010] [Accepted: 02/12/2010] [Indexed: 01/19/2023]
Abstract
A previous report describes that neuropeptide Y (NPY)/NPY2 receptor (NPY2R) is involved in stress-induced visceral obesity. This is a report clarifying the effect on metabolic parameters of single nucleotide polymorphisms in the 5'-flanking region of NPY2R gene. Study participants are 317 people (98 men and 219 women, 40-79 years old) undergoing health checkups. The single nucleotide polymorphism typing of rs6857715 and rs6857530 located on the 5'-flanking region of the NPY2R gene was performed using allele-specific polymerase chain reaction method. Serum high-density lipoprotein cholesterol (HDL-C) level was significantly lower in men possessing rs6857715 TT genotype compared with CC and in men possessing rs6857530 GG genotype compared with AA. No significant difference was observed between each genotype and other metabolic parameters including body mass index, waist circumference, systolic and diastolic blood pressure, serum low-density lipoprotein cholesterol, triglyceride, and fasting plasma glucose. The variation in the 5'-flanking region of the NPY2R gene was associated with serum HDL-C level in men and was a predictor for serum HDL-C level independent of sex and serum triglyceride level.
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Affiliation(s)
- Etsuko Takiguchi
- Division of Physiology and Metabolism, University of Hyogo, Akashi 673-8588, Japan
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Christopoulos P, Mastorakos G, Gazouli M, Deligeoroglou E, Katsikis I, Diamanti-Kandarakis E, Panidis D, Creatsas G. Peroxisome proliferator-activated receptor-γ and -δ polymorphisms in women with polycystic ovary syndrome. Ann N Y Acad Sci 2010; 1205:185-91. [DOI: 10.1111/j.1749-6632.2010.05647.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Abstract
Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/ß and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones.
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Affiliation(s)
- Salman Azhar
- Geriatric Research, Education & Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, USA.
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San-Millán JL, Escobar-Morreale HF. The role of genetic variation in peroxisome proliferator-activated receptors in the polycystic ovary syndrome (PCOS): an original case-control study followed by systematic review and meta-analysis of existing evidence. Clin Endocrinol (Oxf) 2010; 72:383-92. [PMID: 19681917 DOI: 10.1111/j.1365-2265.2009.03679.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To study the association of polymorphisms in the genes encoding peroxisome proliferator-activated receptors (PPARs) with the polycystic ovary syndrome (PCOS). DESIGN Case-control study and meta-analysis of published evidence. PATIENTS One hundred and sixty-one polycystic ovary syndrome patients and 113 non-hyperandrogenic women. MEASUREMENTS Genotyping for PPAR-gamma coactivator-1 gene (PPARGC1A) Gly482Ser, PPAR-alpha Leu162Val, PPAR-delta rs2267668A/G, PPAR-delta-87T/C, PPAR-gamma2 Pro12Ala and PPAR-gamma2 -681C/G variants and systematic review of the literature using the Entrez-PubMed search engine, followed by meta-analysis whenever possible. RESULTS Polycystic ovary syndrome patients carried the Gly482Ser variant in PPARGC1A more frequently than controls (72%vs. 58%, chi(2 )=( )5.54 P = 0.019), whereas carriers of the PPAR-alpha Leu162Val, PPAR-delta rs2267668A/G, PPAR-delta-87T/C, PPAR-gamma2 Pro12Ala and PPAR-gamma2 -681C/G variants were distributed similarly among both groups. The interaction between the PPARGC1A Gly482Ser and PPAR-delta-87T/C variants was also associated with PCOS (OR = 1.24, 95% CI 1.05-1.50, P = 0.008). The systematic review identified 31 studies addressing associations between PPARs variants and PCOS; meta-analysis was possible for nine studies focusing on the PPAR-gamma2 Pro12Ala variant. Although the individual studies did not reveal any statistically significant association, meta-analysis uncovered that carrying the PPAR-gamma2 Pro12Ala variant was associated with a reduced probability of having PCOS (OR = 0.77, 95% CI 0.61-0.96, P = 0.025), and that this association may be mediated by an effect on insulin sensitivity. CONCLUSIONS Common polymorphisms in the PPARGC1A, PPAR-delta and PPAR-gamma2 loci are associated with PCOS.
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Affiliation(s)
- José L San-Millán
- Department of Molecular Genetics, Hospital Universitario Ramon y Cajal & Universidad de Alcala, Madrid, Spain
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Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev 2009; 61:373-93. [PMID: 19805479 DOI: 10.1124/pr.109.001560] [Citation(s) in RCA: 160] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Agonists directed against the alpha and gamma isoforms of the peroxisome proliferator-activated receptors (PPARs) have become important for the respective treatment of hypertriglyceridemia and insulin resistance associated with metabolic disease. PPARdelta is the least well characterized of the three PPAR isoforms. Skeletal muscle insulin resistance is a primary risk factor for the development of type 2 diabetes. There is increasing evidence that PPARdelta is an important regulator of skeletal muscle metabolism, in particular, muscle lipid oxidation, highlighting the potential utility of this isoform as a drug target. In addition, PPARdelta seems to be a key regulator of skeletal muscle fiber type and a possible mediator of the adaptations noted in skeletal muscle in response to exercise. In this review we summarize the current status regarding the regulation, and the metabolic effects, of PPARdelta in skeletal muscle.
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Affiliation(s)
- Ewa Ehrenborg
- Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Nohara A, Kobayashi J, Mabuchi H. Retinoid X receptor heterodimer variants and cardiovascular risk factors. J Atheroscler Thromb 2009; 16:303-18. [PMID: 19672026 DOI: 10.5551/jat.no786] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis.This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.
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Affiliation(s)
- Atsushi Nohara
- Departments of Lipidology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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Karpe F, Ehrenborg EE. PPARdelta in humans: genetic and pharmacological evidence for a significant metabolic function. Curr Opin Lipidol 2009; 20:333-6. [PMID: 19512923 DOI: 10.1097/mol.0b013e32832dd4b1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Abundant data in rodents suggest an important role for peroxisomal proliferators-activated receptor-delta (PPARdelta) in regulating skeletal muscle fatty acid oxidation and this has consequences for lipid and lipoprotein metabolism. Considerably less is known in humans and this review will focus on evidence derived from studies of the PPARD gene and pharmacological use of specific PPARdelta agonists. RECENT FINDINGS Genetic association studies of single-nucleotide polymorphisms in the PPARD gene have only provided negative or conflicting evidence for gross phenotypes such as obesity, hyperlipidaemia and type 2 diabetes. This does not exclude more subtle effects in skeletal muscle metabolic function, but studies of this type need replication. A couple of recent studies using the specific PPARdelta agonist GW501516 suggest potent hypolipidaemic actions, presumably caused by enhanced fat oxidation in skeletal muscle. SUMMARY Considering the hypolipidaemic effect in humans by PPARdelta agonists, long-term studies are needed to confirm efficacy and safety.
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Affiliation(s)
- Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, UK.
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Abstract
Peroxisome proliferator-activated receptors belong to the superfamily of ligand-dependent nuclear receptor transcription factors, which include three subtypes: PPAR-α, β/δ, and γ. PPAR-δ, play important roles in the regulation of cell growth and differentiation as well as tissue wound and repair. Emerging evidence has also demonstrated that PPAR-δ is implicated in lipids and glucose metabolism. Most recently, the direct effects of PPAR-δ on cardiovascular processes such as endothelial function and angiogenesis have also been investigated. Therefore, it is suggested that PPAR-δ may have critical roles in cardiovascular pathophysiology and is a potential target for therapeutic intervention of cardiovascular disorders such as atherosclerosis.
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Sáez ME, Grilo A, Morón FJ, Manzano L, Martínez-Larrad MT, González-Pérez A, Serrano-Hernando J, Ruiz A, Ramírez-Lorca R, Serrano-Ríos M. Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity. Cardiovasc Diabetol 2008; 7:23. [PMID: 18657264 PMCID: PMC2527300 DOI: 10.1186/1475-2840-7-23] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 07/25/2008] [Indexed: 11/10/2022] Open
Abstract
Context Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. Objective To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. Design Cross-sectional, genetic association study and gene-gene interaction analysis. Subjects The study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30) and 1228 non obese subjects. Results In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%. Conclusion Our results suggest that CAPN5 and PPARD gene products may also interact in vivo.
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Affiliation(s)
- María E Sáez
- Departamento de Genómica Estructural, Neocodex, C/.,Charles Darwin 6, Acc. A, 41092, Sevilla, Spain.
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Kaji H, Fukano C, Kimura Y, Takiguchi E, Tanida K. Genetic variations at the CCAAT/enhancer-binding protein delta are associated with metabolic phenotypes in the Japanese population. Metab Syndr Relat Disord 2008; 6:24-31. [PMID: 18370833 DOI: 10.1089/met.2007.0022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Expression of CCAAT/enhancer-binding protein delta (C/EBP-delta) gene is enhanced in the early initial stage of adipocyte differentiation. This study is intended to elucidate the association between the genetic variation of C/EBP-delta and metabolic phenotypes. SUBJECTS AND METHODS Subjects were unselected 52 males and 120 females in Japan, aged 40 to 79 years, who visited a city hygienic center for a health checkup and agreed to participation in the study after giving informed consent. The C/EBP-delta genotypes and metabolic phenotypes were determined. An association study was performed using Pearson's chi(2) tests and logistic regression analyses. RESULTS Two SNPs in C/EBP-delta gene with minor allele frequency greater than 0.05 were detectable among seven SNPs. Genotype heterozygous for the C and T allele (877C/T) were more prevalent in subjects with dyslipidemia [plasma triglyceride (TG) > or =150 mg/dL and/or plasma high-density lipoprotein-cholesterol (HDL-C) <40 mg/dL] as well as high fasting plasma glucose (FPG; > or =110 mg/dL) than controls (22.5% vs. 7.6%, P = 0.009, and 20.0% vs. 8.4%, P = 0.041, respectively). Moreover, the genotype 877C/T contributed to both dyslipidemia and high FPG independent of age, sex, and visceral obesity. Regarding 394C>G, no association between the genotype and metabolic phenotypes was detected. CONCLUSION Results suggest that genetic variations in the C/EBP-delta might play a role in some metabolic phenotypes.
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Affiliation(s)
- Hidesuke Kaji
- Division of Physiology and Metabolism, University of Hyogo, Akashi, Japan.
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Yong EL, Li J, Liu MH. Single gene contributions: genetic variants of peroxisome proliferator-activated receptor (isoforms alpha, beta/delta and gamma) and mechanisms of dyslipidemias. Curr Opin Lipidol 2008; 19:106-12. [PMID: 18388689 DOI: 10.1097/mol.0b013e3282f64542] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW Polymorphisms in peroxisome proliferator-activated receptor isoforms may be among the most important single-gene contributors to dyslipidemias, insulin resistance, and maturity-onset diabetes. RECENT FINDINGS Familial partial lipodystrophy is a rare but characteristic phenotype associated with carriers of peroxisome proliferator-activated receptor-gamma missense mutations. Mutant receptors are transcriptionally defective, exhibit aberrant affinity for co-regulator molecules, and can exert dominant-negative or haplo-insufficiency effects on normal peroxisome proliferator-activated receptor-gamma function. The P12A variant of isoform gamma is estimated to reduce diabetes risk by 19% in many populations, and has a large attributable risk because of high prevalence of the normal allele. Variants L162V and V227A of isoform alpha (common in white and Oriental populations, respectively) are associated with sexually dimorphic perturbations of lipid metabolism and cardiovascular risk. Polymorphisms in isoforms alpha and beta/delta are reported to influence lipid and glucose utilization. Apart from lipodystrophic syndromes, metabolic and cardiovascular risk in peroxisome proliferator-activated receptor variants is apparently modulated by dietary and exercise interventions, and interactions with polymorphisms in other genetic loci. SUMMARY Polymorphisms in peroxisome proliferator-activated receptors are critical susceptibility risk factors for dyslipidemias and diabetes. They provide attractive targets for gene-environment interventions to reduce the burden of metabolic disease.
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Affiliation(s)
- Eu Leong Yong
- Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore.
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Abstract
PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPAR delta to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPAR delta represents a novel therapeutic target and the development of PPAR delta gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome.
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Affiliation(s)
- Shannon M Reilly
- Department of Genetics and Complex Diseases, Harvard University School of Public Health, 665 Huntington Avenue, Bldg 2, Room 119, Boston, MA 02115-5818, USA
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Abstract
The goal of pharmacogenetics is to define the genetic determinants of individual drug responsiveness, and thereby provide personalized treatment to each individual. The peroxisome proliferator-activated receptors (PPARs) are polypeptide products of a set of related genes functioning to regulate several cellular processes that are central to cardiovascular health and disease. Given their pleiotropic roles in lipid and glucose homeostasis, cardiac energy balance and regulation of adipocyte release of circulating inflammatory factors, it is not surprising that PPARs represent an attractive target for clinical investigation and intervention in disease states, such as diabetes, obesity, atherosclerosis, cardiomyopathy, cardiac hypertrophy and heart failure. Research into the manipulation of PPAR function by pharmacologic agents has already resulted in important advances in the treatment of diabetes mellitus and cardiovascular disease. It follows that PPAR pharmacogenetics promises important advances in the personalized treatment of cardiovascular disease.
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Affiliation(s)
- Sharon Cresci
- Washington University School of Medicine, Department of Medicine, Saint Louis, Missouri, 660 South Euclid Avenue, Campus Box 8086 Saint Louis, MO 63110-1093, USA
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