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Yilmaz-Aydogan H, Kanca-Demirci D, Gul N, Aydogan C, Poyrazoglu S, Tutuncu Y, Malikova F, Ozturk O, Satman I. Target gene variations of PPAR isoforms may contribute to MODY heterogeneity: A preliminary comparative study with type 2 diabetes. Diabetes Res Clin Pract 2024; 218:111932. [PMID: 39551189 DOI: 10.1016/j.diabres.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/30/2024] [Accepted: 11/11/2024] [Indexed: 11/19/2024]
Abstract
AIMS The objective of this study was to evaluate the associations of several genetic variants of peroxisome proliferator-activated receptors (PPARs) on clinical and laboratory parameters in patients with maturity-onset diabetes of the young (MODY), and possible contribution to heterogeneity of the disease. METHODS The study groups comprised patients with MODY (genetically confirmed (n = 28), clinically relevant but genetically unconfirmed; MODYX (n = 56)), type 2 diabetes mellitus (T2DM; n = 94) and healthy controls (n = 153). PPARA-L162V-(rs1800206), PPARG-C161T-(rs3856806), P12A-(rs1801282), and PPARB/D + 294 T/C-(rs2016520) polymorphisms were genotyped by real-time-PCR. RESULTS The results demonstrated that the frequencies of PPARA-LL162 (p = 0.002), PPARG-CC161 (p = 0.002), and PPARG-ProPro (p = 0.012) genotypes were significantly higher in the MODY group compared to the controls. Furthermore, total-MODY and MODYX groups had a higher frequency of PPARA-LL162 genotype than T2DM (p = 0.005 and p = 0.006, respectively). The frequency of the PPARB/D + 294 T allele was significantly higher in individuals with T2DM than in genetically-determined MODY group (p = 0.019). The PPARA-LL162 genotype was associated with early-onset diabetes in total-MODY (p = 0.022) and T2DM (p < 0.05) groups. CONCLUSIONS The association of PPARA-L162V polymorphism with early-onset diabetes in both T2DM and MODY is a noteworthy finding. Considering these results, we suggested that genetic polymorphisms in PPAR isoforms may contribute to the clinical and metabolic heterogeneity of MODY.
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Affiliation(s)
- Hulya Yilmaz-Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Deniz Kanca-Demirci
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye; Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Halic University, Istanbul, Türkiye.
| | - Nurdan Gul
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
| | - Cagatay Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Sukran Poyrazoglu
- Pediatric Endocrinology Unit, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
| | - Yıldız Tutuncu
- Department of KUTTAM Immunology, Faculty of Medicine, Koc University, Istanbul, Türkiye.
| | - Fidan Malikova
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Oguz Ozturk
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Ilhan Satman
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
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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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Valverde-Hernández JC, Flores-Cruz A, Chavarría-Soley G, Silva de la Fuente S, Campos-Sánchez R. Frequencies of variants in genes associated with dyslipidemias identified in Costa Rican genomes. Front Genet 2023; 14:1114774. [PMID: 37065472 PMCID: PMC10098023 DOI: 10.3389/fgene.2023.1114774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/14/2023] [Indexed: 04/18/2023] Open
Abstract
Dyslipidemias are risk factors in diseases of significant importance to public health, such as atherosclerosis, a condition that contributes to the development of cardiovascular disease. Unhealthy lifestyles, the pre-existence of diseases, and the accumulation of genetic variants in some loci contribute to the development of dyslipidemia. The genetic causality behind these diseases has been studied primarily on populations with extensive European ancestry. Only some studies have explored this topic in Costa Rica, and none have focused on identifying variants that can alter blood lipid levels and quantifying their frequency. To fill this gap, this study focused on identifying variants in 69 genes involved in lipid metabolism using genomes from two studies in Costa Rica. We contrasted the allelic frequencies with those of groups reported in the 1000 Genomes Project and gnomAD and identified potential variants that could influence the development of dyslipidemias. In total, we detected 2,600 variants in the evaluated regions. However, after various filtering steps, we obtained 18 variants that have the potential to alter the function of 16 genes, nine variants have pharmacogenomic or protective implications, eight have high risk in Variant Effect Predictor, and eight were found in other Latin American genetic studies of lipid alterations and the development of dyslipidemia. Some of these variants have been linked to changes in blood lipid levels in other global studies and databases. In future studies, we propose to confirm at least 40 variants of interest from 23 genes in a larger cohort from Costa Rica and Latin American populations to determine their relevance regarding the genetic burden for dyslipidemia. Additionally, more complex studies should arise that include diverse clinical, environmental, and genetic data from patients and controls and functional validation of the variants.
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Affiliation(s)
| | - Andrés Flores-Cruz
- Centro de Investigación en Biología Celular y Molecular, University of Costa Rica, San José, Costa Rica
| | - Gabriela Chavarría-Soley
- Centro de Investigación en Biología Celular y Molecular, University of Costa Rica, San José, Costa Rica
- Escuela de Biología, University of Costa Rica, San José, Costa Rica
| | - Sandra Silva de la Fuente
- Centro de Investigación en Biología Celular y Molecular, University of Costa Rica, San José, Costa Rica
| | - Rebeca Campos-Sánchez
- Centro de Investigación en Biología Celular y Molecular, University of Costa Rica, San José, Costa Rica
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4
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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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Identification of crucial hub genes and potential molecular mechanisms in breast cancer by integrated bioinformatics analysis and experimental validation. Comput Biol Med 2022; 149:106036. [DOI: 10.1016/j.compbiomed.2022.106036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 08/14/2022] [Accepted: 08/20/2022] [Indexed: 11/24/2022]
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Aronica L, Volek J, Poff A, D'agostino DP. Genetic variants for personalised management of very low carbohydrate ketogenic diets. BMJ Nutr Prev Health 2020; 3:363-373. [PMID: 33521546 PMCID: PMC7841814 DOI: 10.1136/bmjnph-2020-000167] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/04/2020] [Accepted: 11/15/2020] [Indexed: 01/07/2023] Open
Abstract
The ketogenic diet (KD) is a low-carbohydrate, high-fat, adequate-protein diet proven to be effective for the reversal of obesity, metabolic syndrome and type 2 diabetes, and holding therapeutic potential for the prevention and treatment of other chronic diseases. Genetic and dynamic markers of KD response may help to identify individuals most likely to benefit from KD and point to individuals at higher risk for adverse health outcomes. Here, we provide a clinician-friendly review of state-of-the-art research on biomarkers of KD response for a variety of outcomes including weight loss, body composition and cognitive performance drawing data from both intervention trials and case reports of rare inborn errors of metabolism. We also present a selection of the most promising candidate genes to evaluate in future studies and discuss key aspects of study design and variant interpretation that may help accelerate the implementation of these biomarkers in clinical practice.
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Affiliation(s)
- Lucia Aronica
- Nutrition Science, Metagenics Inc, Gig Harbor, Washington, USA.,Medicine, Stanford University, Stanford, California, USA
| | - Jeff Volek
- Human Sciences, The Ohio State University, Columbus, Ohio, USA
| | - Angela Poff
- Medicine Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida, USA
| | - Dominic P D'agostino
- Medicine Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida, USA
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Guan CY, Tian S, Cao JL, Wang XQ, Ma X, Xia HF. Down-Regulated miR-21 in Gestational Diabetes Mellitus Placenta Induces PPAR-α to Inhibit Cell Proliferation and Infiltration. Diabetes Metab Syndr Obes 2020; 13:3009-3034. [PMID: 32943895 PMCID: PMC7455759 DOI: 10.2147/dmso.s253920] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022] Open
Abstract
PURPOSE This study aimed to investigate the role of miR-21 expression in the reduction of placental function in GDM patients. MATERIALS AND METHODS qRT-PCR was used to detect the differential expression of miR-21 in the serum of gestational diabetes mellitus (GDM) and normal pregnant women, and to verify the functional target gene PPAR-α of miR-21 by double fluorescence experiments. Cellular experiments were performed to verify the effect of PPAR-α on cell function. RESULTS miR-21 is down-regulated in the serum and placenta of GDM patients compared to normal pregnant women. In the case of insulin resistance, miR-21-5p knockdown promoted glucose uptake, but no significant effect was found under physiological condition. Functional studies have shown that reduced PPAR-α expression can restore miR-21 knockdown-mediated cell growth and metastasis inhibition. Additionally, decreased expression of miR-21 but increased expression of -PPAR-α was observed in patients with GDM and GDM rats. CONCLUSION The expression of the placental miR-21-5p, which inhibits cell growth and infiltration by up-regulating PPAR-α, is downregulated in pregnant GDM patients, which in turn may affect the placental function.
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Affiliation(s)
- Chun-Yi Guan
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing100081, People’s Republic of China
- Graduate School, Peking Union Medical College, Beijing Province100005, People’s Republic of China
| | - Shi Tian
- Haidian Maternal & Child Health Hospital, Beijing100080, People’s Republic of China
| | - Jing-Li Cao
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing100081, People’s Republic of China
- Graduate School, Peking Union Medical College, Beijing Province100005, People’s Republic of China
| | - Xue-Qin Wang
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing100081, People’s Republic of China
- Graduate School, Peking Union Medical College, Beijing Province100005, People’s Republic of China
| | - Xu Ma
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing100081, People’s Republic of China
- Graduate School, Peking Union Medical College, Beijing Province100005, People’s Republic of China
| | - Hong-Fei Xia
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing100081, People’s Republic of China
- Graduate School, Peking Union Medical College, Beijing Province100005, People’s Republic of China
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8
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Impact of PPAR-Alpha Polymorphisms-The Case of Metabolic Disorders and Atherosclerosis. Int J Mol Sci 2019; 20:ijms20184378. [PMID: 31489930 PMCID: PMC6770475 DOI: 10.3390/ijms20184378] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/01/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
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Maciejewska-Skrendo A, Buryta M, Czarny W, Król P, Stastny P, Petr M, Safranow K, Sawczuk M. The Polymorphisms of the Peroxisome-Proliferator Activated Receptors' Alfa Gene Modify the Aerobic Training Induced Changes of Cholesterol and Glucose. J Clin Med 2019; 8:jcm8071043. [PMID: 31319591 PMCID: PMC6679124 DOI: 10.3390/jcm8071043] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/09/2019] [Accepted: 07/15/2019] [Indexed: 12/19/2022] Open
Abstract
Background: PPARα is a transcriptional factor that controls the expression of genes involved in fatty acid metabolism, including fatty acid transport, uptake by the cells, intracellular binding, and activation, as well as catabolism (particularly mitochondrial fatty acid oxidation) or storage. PPARA gene polymorphisms may be crucial for maintaining lipid homeostasis and in this way, being responsible for developing specific training-induced physiological reactions. Therefore, we have decided to check if post-training changes of body mass measurements as well as chosen biochemical parameters are modulation by the PPARA genotypes. Methods: We have examined the genotype and alleles’ frequencies (described in PPARA rs1800206 and rs4253778 polymorphic sites) in 168 female participants engaged in a 12-week training program. Body composition and biochemical parameters were measured before and after the completion of a whole training program. Results: Statistical analyses revealed that PPARA intron 7 rs4253778 CC genotype modulate training response by increasing low-density lipoproteins (LDL) and glucose concentration, while PPARA Leu162Val rs1800206 CG genotype polymorphism interacts in a decrease in high-density lipoproteins (HDL) concentration. Conclusions: Carriers of PPARA intron 7 rs4253778 CC genotype and Leu162Val rs1800206 CG genotype might have potential negative training-induced cholesterol and glucose changes after aerobic exercise.
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Affiliation(s)
- Agnieszka Maciejewska-Skrendo
- Department of Molecular Biology, Faculty of Physical Education, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland
| | - Maciej Buryta
- Department of Molecular Biology, Faculty of Physical Education, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland
| | - Wojciech Czarny
- Department of Anatomy and Anthropology, Faculty of Physical Education, University of Rzeszow, 35-310 Rzeszow, Poland
| | - Pawel Król
- Department of Anatomy and Anthropology, Faculty of Physical Education, University of Rzeszow, 35-310 Rzeszow, Poland
| | - Petr Stastny
- Department of Sport Games, Faulty of Physical Education and Sport, Charles University, 162-52 Prague, Czech Republic.
| | - Miroslav Petr
- Department of Sport Games, Faulty of Physical Education and Sport, Charles University, 162-52 Prague, Czech Republic
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Marek Sawczuk
- Unit of Physical Medicine, Faculty of Tourism and Recreation, Gdansk University of Physical Education and Sport, 80-336 Gdansk, Poland
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Genetic Risk Score Predictive of the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation in a Mexican Population. Nutrients 2019; 11:nu11040737. [PMID: 30934900 PMCID: PMC6521301 DOI: 10.3390/nu11040737] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 03/26/2019] [Accepted: 03/28/2019] [Indexed: 12/24/2022] Open
Abstract
Our group built a genetic risk score (GRS) of the plasma triglyceride (TG) response to an omega-3 (n-3) fatty acid (FA) supplementation in Caucasian Canadians that explained 21.53% of the TG variance. The objective was to refine the GRS by fine mapping and to test its association with the TG response in young Mexican adults. A total of 191 participants underwent a 6-week n-3 FA supplementation providing 2.7g/day of docosahexaenoic and eicosapentaenoic acids. Using quantitative polymerase chain reaction (PCR), 103 single-nucleotide polymorphisms (SNPs) were genotyped. A stepwise regression adjusted for age, sex, and body mass index (BMI) was used to select the strongest SNPs to include in the genetic risk model. A GRS was calculated from the sum of at-risk alleles. The contribution of the GRS to the TG response was assessed by ANCOVA with age, sex, and BMI included in the model. Several differences in allele frequency were observed between Canadians and Mexicans. Five lead SNPs were included in the genetic risk model, in which the GRS accounted for 11.01% of the variance of the TG response (p < 0.0001). These findings highlight the important contribution of genetic factors to the heterogeneity of the TG response to an n-3 FA supplementation among Mexicans.
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Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, De Bosscher K. Molecular Actions of PPARα in Lipid Metabolism and Inflammation. Endocr Rev 2018; 39:760-802. [PMID: 30020428 DOI: 10.1210/er.2018-00064] [Citation(s) in RCA: 532] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 07/10/2018] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
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Affiliation(s)
- Nadia Bougarne
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Basiel Weyers
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Sofie J Desmet
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Julie Deckers
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation, VIB Center for Inflammation Research, Ghent (Zwijnaarde), Belgium
| | - David W Ray
- Division of Metabolism and Endocrinology, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Bart Staels
- Université de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
- INSERM, U1011, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
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12
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Phenotype and genotype predictors of BMI variability among European adults. Nutr Diabetes 2018; 8:27. [PMID: 29795275 PMCID: PMC5966508 DOI: 10.1038/s41387-018-0041-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/14/2018] [Accepted: 04/09/2018] [Indexed: 01/13/2023] Open
Abstract
Background/Objective Obesity is a complex and multifactorial disease resulting from the interactions among genetics, metabolic, behavioral, sociocultural and environmental factors. In this sense, the aim of the present study was to identify phenotype and genotype variables that could be relevant determinants of body mass index (BMI) variability. Subjects/Methods In the present study, a total of 1050 subjects (798 females; 76%) were included. Least angle regression (LARS) analysis was used as regression model selection technique, where the dependent variable was BMI and the independent variables were age, sex, energy intake, physical activity level, and 16 polymorphisms previously related to obesity and lipid metabolism. Results The LARS analysis obtained the following formula for BMI explanation: (64.7 + 0.10 × age [years] + 0.42 × gender [0, men; 1, women] + −40.6 × physical activity [physical activity level] + 0.004 × energy intake [kcal] + 0.74 × rs9939609 [0 or 1–2 risk alleles] + −0.72 × rs1800206 [0 or 1–2 risk alleles] + −0.86 × rs1801282 [0 or 1–2 risk alleles] + 0.87 × rs429358 [0 or 1–2 risk alleles]. The multivariable regression model accounted for 21% of the phenotypic variance in BMI. The regression model was internally validated by the bootstrap method (r2 original data set = 0.208, mean r2 bootstrap data sets = 0.210). Conclusion In conclusion, age, physical activity, energy intake and polymorphisms in FTO, APOE, PPARG and PPARA genes are significant predictors of the BMI trait.
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13
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Corton JC, Peters JM, Klaunig JE. The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions. Arch Toxicol 2017; 92:83-119. [PMID: 29197930 DOI: 10.1007/s00204-017-2094-7] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/12/2017] [Indexed: 12/17/2022]
Abstract
A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. The weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis is summarized here. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators. The key events (KE) identified in the MOA are PPARα activation (KE1), alteration in cell growth pathways (KE2), perturbation of hepatocyte growth and survival (KE3), and selective clonal expansion of preneoplastic foci cells (KE4), which leads to the apical event-increases in hepatocellular adenomas and carcinomas (KE5). In addition, a number of concurrent molecular and cellular events have been classified as modulating factors, because they potentially alter the ability of PPARα activators to increase rodent liver cancer while not being key events themselves. These modulating factors include increases in oxidative stress and activation of NF-kB. PPARα activators are unlikely to induce liver tumors in humans due to biological differences in the response of KEs downstream of PPARα activation. This conclusion is based on minimal or no effects observed on cell growth pathways and hepatocellular proliferation in human primary hepatocytes and absence of alteration in growth pathways, hepatocyte proliferation, and tumors in the livers of species (hamsters, guinea pigs and cynomolgus monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Despite this overwhelming body of evidence and almost universal acceptance of the PPARα MOA and lack of human relevance, several reviews have selectively focused on specific studies that, as discussed, contradict the consensus opinion and suggest uncertainty. In the present review, we systematically address these most germane suggested weaknesses of the PPARα MOA.
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Affiliation(s)
- J Christopher Corton
- Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr, MD-B105-03, Research Triangle Park, NC, 27711, USA.
| | - Jeffrey M Peters
- The Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16803, USA
| | - James E Klaunig
- Department of Environmental Health, Indiana University, Bloomington, IN, 47402, USA
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Lianggeng X, Baiwu L, Maoshu B, Jiming L, Youshan L. Impact of Interaction Between PPAR Alpha and PPAR Gamma on Breast Cancer Risk in the Chinese Han Population. Clin Breast Cancer 2017; 17:336-340. [DOI: 10.1016/j.clbc.2016.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 08/15/2016] [Accepted: 10/12/2016] [Indexed: 12/11/2022]
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Improvement of cardiometabolic markers after fish oil intervention in young Mexican adults and the role of PPARα L162V and PPARγ2 P12A. J Nutr Biochem 2017; 43:98-106. [PMID: 28282585 DOI: 10.1016/j.jnutbio.2017.02.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 12/03/2016] [Accepted: 02/07/2017] [Indexed: 11/20/2022]
Abstract
Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and indicators for glucose metabolism, circulating lipids, and markers for inflammation were analyzed before and after intervention. An overall decrease in triglycerides (TG) and an increase in HS-ω3 index were observed in all subjects [-4.1 mg/dL, (SD:±51.7), P=.02 and 2.6%, (SD:±1.2), P<.001 respectively]. Mean fasting insulin and glycated hemoglobin (HbA1c%) were significantly decreased in all subjects [-0.547mlU/L, (SD:±10.29), P=.034 and-0.07%, (SD:±0.3), P<.001 respectively], whereas there was no change in body composition, fasting glucose, adiponectin and inflammatory markers. Subjects carrying the minor alleles of PPARα L162V and PPARγ2 P12A had higher responses in reduction of TG and fasting insulin respectively. Interestingly, doses below 2.7 g/day (1.8 g/day) were sufficient to induce a significant reduction in fasting insulin and HbA1c% from baseline (P=.019 and P<.001). The observed responses in triglycerides and fasting insulin in the Mexican population give further evidence of the importance of FO supplementation in young people as an early step towards the prevention of cardiometabolic disease.
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Vallée Marcotte B, Guénard F, Cormier H, Lemieux S, Couture P, Rudkowska I, Vohl MC. Plasma Triglyceride Levels May Be Modulated by Gene Expression of IQCJ, NXPH1, PHF17 and MYB in Humans. Int J Mol Sci 2017; 18:ijms18020257. [PMID: 28134766 PMCID: PMC5343793 DOI: 10.3390/ijms18020257] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 01/12/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023] Open
Abstract
A genome-wide association study (GWAS) by our group identified loci associated with the plasma triglyceride (TG) response to ω-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. Our aim is to investigate potential mechanisms underlying the associations between single nucleotide polymorphisms (SNPs) in the four genes and TG levels following ω-3 FA supplementation. 208 subjects received 3 g/day of ω-3 FA (1.9–2.2 g of EPA and 1.1 g of docosahexaenoic acid (DHA)) for six weeks. Plasma TG were measured before and after the intervention. 67 SNPs were selected to increase the density of markers near GWAS hits. Genome-wide expression and methylation analyses were conducted on respectively 30 and 35 participants’ blood sample together with in silico analyses. Two SNPs of IQCJ showed different affinities to splice sites depending on alleles. Expression levels were influenced by genotype for one SNP in NXPH1 and one in MYB. Associations between 12 tagged SNPs of IQCJ, 26 of NXPH1, seven of PHF17 and four of MYB and gene-specific CpG site methylation levels were found. The response of plasma TG to ω-3 FA supplementation may be modulated by the effect of DNA methylation on expression levels of genes revealed by GWAS.
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Affiliation(s)
- Bastien Vallée Marcotte
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
| | - Frédéric Guénard
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
| | - Hubert Cormier
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
| | - Simone Lemieux
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
| | - Patrick Couture
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
- CHU de Québec Research Center-Endocrinology and Nephrology, 2705 Laurier Blvd, Quebec, QC G1V 4G2, Canada.
| | - Iwona Rudkowska
- CHU de Québec Research Center-Endocrinology and Nephrology, 2705 Laurier Blvd, Quebec, QC G1V 4G2, Canada.
| | - Marie-Claude Vohl
- Institute of Nutrition and Functional Foods (INAF), Laval University, 2440 Hochelaga Blvd, Quebec, QC G1V 0A6, Canada.
- CHU de Québec Research Center-Endocrinology and Nephrology, 2705 Laurier Blvd, Quebec, QC G1V 4G2, Canada.
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Feng F, Wu J, Gao Z, Yu S, Cui Y. Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships. Medicine (Baltimore) 2017; 96:e5679. [PMID: 28072703 PMCID: PMC5228663 DOI: 10.1097/md.0000000000005679] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC.The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA-DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co-regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA-DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA-TF regulation network.A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA-DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co-regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA-TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR-1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP-responsive element modulator (CREM) were the critical regulated TFs.Four up-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM.
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Wang Y, Yin X, Li L, Deng S, He Z. Association of Apolipoprotein C3 Genetic Polymorphisms with the Risk of Ischemic Stroke in the Northern Chinese Han Population. PLoS One 2016; 11:e0163910. [PMID: 27690381 PMCID: PMC5045204 DOI: 10.1371/journal.pone.0163910] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/18/2016] [Indexed: 12/16/2022] Open
Abstract
The apolipoprotein C3 (APOC3) gene, which is a member of the APOA1/C3/A4/A5 gene cluster, plays a crucial role in lipid metabolism. Dyslipidemia is an important risk factor for ischemic stroke. In the present study, we performed a hospital-based case-control study of 895 ischemic stroke patients and 883 control subjects to examine the effects of four APOC3 single nucleotide polymorphisms (SNPs) (rs2854116, rs2854117, rs4520 and rs5128) on the risk of ischemic stroke in a northern Chinese Han population. The SNaPshot Multiplex sequencing assay was used for SNP genotyping, and the potential association of genotype distributions and allele frequencies with ischemic stroke was analyzed statistically. Compared with the GG genotype, the CC+GC genotype of rs5128 was significantly associated with an increased risk in females (adjusted OR = 3.38, 95% CI = 1.82-6.28, P <0.01) after all of the risk factors were adjusted for with logistic regression analyses. A similar relationship was found between the rs4520 polymorphism and ischemic stroke risk in Han Chinese women. Under a recessive genetic model, the TT+TC genotypes of this variant increased ischemic stroke risk (adjusted OR = 2.05; 95% CI = 1.28-3.29; P <0.01). Haplotype analysis revealed that in males, the T-C-T-C haplotype of rs2854116-rs2854117-rs4520-rs5128 was significantly more frequent in the ischemic stroke group than in the control group (OR = 1.49, 95% CI = 1.18-1.87, P<0.01). The results of our study indicate that the APOC3 polymorphisms contribute to ischemic stroke susceptibility in females in the northern Chinese Han population.
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Affiliation(s)
- Yanzhe Wang
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Xiaoyu Yin
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Lei Li
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Shumin Deng
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Zhiyi He
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
- * E-mail:
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Rana S, Kumar S, Rathore N, Padwad Y, Bhushana S. Nutrigenomics and its Impact on Life Style Associated Metabolic Diseases. Curr Genomics 2016; 17:261-78. [PMID: 27252592 PMCID: PMC4869012 DOI: 10.2174/1389202917666160202220422] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 06/18/2015] [Accepted: 06/22/2015] [Indexed: 02/07/2023] Open
Abstract
Post-human genome revelation observes the emergence of 'Nutigenomics' as one of the exciting scientific advancement influencing mankind around the world. Food or more precisely 'nutrition' has the major impact in defining the cause-response interaction between nutrient (diet) and human health. In addition to substantial understanding of nutrition-human-health interaction, bases of 'nutrigenomic' development foster on advent in transcriptomics, genomics, proteomics and metabolomics as well as insight into food as health supplement. Interaction of selected nutrient with associated genes in specific organ or tissue necessary to comprehend that how individual's genetic makeup (DNA transcribed into mRNA and then to proteins) respond to particular nutrient. It provided new opportunities to incorporate natural bioactive compounds into food for specific group of people with similar genotype. As inception of diabetes associated with change in gene expression of, not limited to, protein kinase B, insulin receptor, duodenal homeobox and glucokinase, thus, targeting such proteins by modifying or improving the nutritional availability or uptake may help to devise novel food, supplements, or nutraceuticals. In this article, various aspects of R&D in nutrigenomics are reviewed to ascertain its impact on human health, especially with life-style associated diseases.
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Affiliation(s)
- Shalika Rana
- Department of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176 061 (HP), India
- Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology,
Palampur176 061 (HP), India
| | - Shiv Kumar
- Pharmacology and Toxicology Lab, Department of Food Nutraceuticals and Quality
Control, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176 061 (HP), India
- Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology,
Palampur176 061 (HP), India
| | - Nikita Rathore
- Department of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176 061 (HP), India
| | - Yogendra Padwad
- Pharmacology and Toxicology Lab, Department of Food Nutraceuticals and Quality
Control, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176 061 (HP), India
- Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology,
Palampur176 061 (HP), India
| | - Shashi Bhushana
- Department of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176 061 (HP), India
- Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology,
Palampur176 061 (HP), India
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Vallée Marcotte B, Cormier H, Guénard F, Rudkowska I, Lemieux S, Couture P, Vohl MC. Novel Genetic Loci Associated with the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation. JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS 2016; 9:1-11. [PMID: 27160456 DOI: 10.1159/000446024] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 04/07/2016] [Indexed: 11/19/2022]
Abstract
BACKGROUND A recent genome-wide association study (GWAS) by our group identified 13 loci associated with the plasma triglyceride (TG) response to omega-3 (n-3) fatty acid (FA) supplementation. This study aimed to test whether single-nucleotide polymorphisms (SNPs) within the IQCJ, NXPH1, PHF17 and MYB genes are associated with the plasma TG response to an n-3 FA supplementation. METHODS A total of 208 subjects followed a 6-week n-3 FA supplementation of 5 g/day of fish oil (1.9-2.2 g of eicosapentaenoic acid and 1.1 g of docosahexaenoic acid). Measurements of plasma lipids were made before and after the supplementation. Sixty-seven tagged SNPs were selected to increase the density of markers near GWAS hits. RESULTS In a repeated model, independent effects of the genotype and the gene-supplementation interaction were associated with plasma TG. Genotype effects were observed with two SNPs of NXPH1, and gene-diet interactions were observed with ten SNPs of IQCJ, four SNPs of NXPH1 and three SNPs of MYB. Positive and negative responders showed different genotype frequencies with nine SNPs of IQCJ, two SNPs of NXPH1 and two SNPs of MYB. CONCLUSION Fine mapping in GWAS-associated loci allowed the identification of SNPs partly explaining the large interindividual variability observed in plasma TG levels in response to an n-3 FA supplementation.
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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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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PPARα regulates tumor progression, foe or friend? Eur J Pharmacol 2015; 765:560-4. [PMID: 26409040 DOI: 10.1016/j.ejphar.2015.09.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 09/15/2015] [Accepted: 09/15/2015] [Indexed: 11/21/2022]
Abstract
PPARα belongs to the peroxisome-proliferator-activated receptors (PPARs) family that consists of PPARα, PPARδ, and PAPRγ. Activation of PPARα by ligands including fatty acids and their derivatives as well as some synthetic compounds regulates tumor progression in various tissues. Activated PPARα inhibits or promotes tumorigenesis depending on the specific tissues, but the molecular mechanism is still unclear. In this review, the recent progress of PPARα regulating tumorigenesis is discussed.
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Oladi M, Nohtani M, Avan A, Mirhafez SR, Tajbakhsh A, Ghasemi F, Asadi A, Elahdadi Salmani M, Mohammadi A, Hoseinzadeh L, Ferns GA, Ghayour Mobarhan M. Impact of the C1431T Polymorphism of the Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) Gene on Fasted Serum Lipid Levels in Patients with Coronary Artery Disease. ANNALS OF NUTRITION AND METABOLISM 2015; 66:149-154. [PMID: 25896411 DOI: 10.1159/000381358] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 02/28/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS The C1431T polymorphism of peroxisome proliferator activated receptor-γ (PPAR-γ) gene is related to diabetes and metabolic-syndrome. However, studies have been inconclusive about its association with coronary artery disease (CAD) and there have been no studies analyzing the association of this polymorphism with fasted-serum-lipid levels in Iranian-individuals with CAD. We investigated the association of PPAR-γ C1431T-polymorphism with CAD and dyslipidaemia in 787 individuals. METHODS Anthropometric-parameters and biochemical-measurements were evaluated, followed by genotyping. The association of the genetic-polymorphisms with CAD and lipid-profile was determined by univariate/multivariate-analyses. RESULTS Patients with CT or CT+TT genotype were at an increased-risk of CAD relative to CC-carriers (adjusted odds ratio: 2.03; 95% confidence interval, 1.01-4.09; p = 0.046). However, in the larger population, CT genotype was present at a higher frequency in the group with a positive angiogram. Furthermore, CT+TT genotypes were associated with an altered fasted-lipid-profile in the initial population sample of patients with a positive angiogram, compared to the group with a negative-angiogram. The angiogram-positive patients carrying the T allele had a significantly higher triglyceride, serum C-reactive protein and fasting-blood-glucose. CONCLUSION We have found the PPAR-γ C1431T polymorphism was significantly associated with fasted serum lipid profile in individuals with angiographically defined CAD. Since accumulating data support the role of PPAR-γ polymorphisms in CAD, further studies are required to investigate the association of this polymorphism with coronary artery disease.
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25
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Goni L, Cuervo M, Milagro FI, Martínez JA. A genetic risk tool for obesity predisposition assessment and personalized nutrition implementation based on macronutrient intake. GENES & NUTRITION 2015; 10:445. [PMID: 25430627 PMCID: PMC4246034 DOI: 10.1007/s12263-014-0445-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 11/19/2014] [Indexed: 11/24/2022]
Abstract
There is little evidence about genetic risk score (GRS)-diet interactions in order to provide personalized nutrition based on the genotype. The aim of the study was to assess the value of a GRS on obesity prediction and to further evaluate the interactions between the GRS and dietary intake on obesity. A total of 711 seekers of a Nutrigenetic Service were examined for anthropometric and body composition measurements and also for dietary habits and physical activity. Oral epithelial cells were collected for the identification of 16 SNPs (related with obesity or lipid metabolism) using DNA zip-coded beads. Genotypes were coded as 0, 1 or 2 according to the number of risk alleles, and the GRS was calculated by adding risk alleles with such a criterion. After being adjusted for gender, age, physical activity and energy intake, the GRS demonstrated that individuals carrying >7 risk alleles had in average 0.93 kg/m(2) of BMI, 1.69 % of body fat mass, 1.94 cm of waist circumference and 0.01 waist-to-height ratio more than the individuals with ≤7 risk alleles. Significant interactions for GRS and the consumption of energy, total protein, animal protein, vegetable protein, total fat, saturated fatty acids, polyunsaturated fatty acids, total carbohydrates, complex carbohydrates and fiber intake on adiposity traits were found after adjusted for confounders variables. The GRS confirmed that the high genetic risk group showed greater values of adiposity than the low risk group and demonstrated that macronutrient intake modifies the GRS association with adiposity traits.
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Affiliation(s)
- Leticia Goni
- />Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />Centre for Nutrition Research, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
| | - Marta Cuervo
- />Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />Centre for Nutrition Research, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Fermín I. Milagro
- />Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />Centre for Nutrition Research, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - J. Alfredo Martínez
- />Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />Centre for Nutrition Research, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain
- />CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
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Nadalin S, Giacometti J, Buretić-Tomljanović A. PPARα-L162V polymorphism is not associated with schizophrenia risk in a Croatian population. Prostaglandins Leukot Essent Fatty Acids 2014; 91:221-5. [PMID: 25087592 DOI: 10.1016/j.plefa.2014.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 06/18/2014] [Accepted: 07/04/2014] [Indexed: 12/24/2022]
Abstract
Disturbances of lipid and glucose metabolism have been repeatedly reported in schizophrenia. A functional L162V polymorphism in peroxisome proliferator-activated receptor alpha (PPARα) gene has been extensively investigated in etiology of abnormal lipid and glucose metabolism, yet not in schizophrenia. We determined whether the schizophrenia risk was associated with L162V polymorphism and we examined the impact of L162V variant on age of onset, and data of psychopathology scores. We also hypothesized that plasma glucose and lipid concentrations in patients may be influenced by L162V polymorphism. Genotype and allele frequencies between 203 patients and 191 controls did not differ significantly. Females heterozygous for the PPARα genotype (L162V) manifested significantly lower negative symptom scores, tended toward an earlier onset, and had significantly greater triglyceride levels. The PPARα-L162V polymorphism is not associated with schizophrenia risk in Croatian population, but it impacts clinical expression of the illness and plasma lipid concentrations in female patients.
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Affiliation(s)
- S Nadalin
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - J Giacometti
- Department of Biotechnology, University of Rijeka, Slavka Krautzeka bb, 51000 Rijeka, Croatia
| | - A Buretić-Tomljanović
- Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
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A genetic variant of PPARA modulates cardiovascular risk biomarkers after milk consumption. Nutrition 2014; 30:1144-50. [DOI: 10.1016/j.nut.2014.02.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/10/2014] [Accepted: 02/14/2014] [Indexed: 11/23/2022]
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Tiwari V, Khokhar M. Mechanism of action of anti-hypercholesterolemia drugs and their resistance. Eur J Pharmacol 2014; 741:156-70. [PMID: 25151024 DOI: 10.1016/j.ejphar.2014.07.048] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 07/23/2014] [Accepted: 07/24/2014] [Indexed: 01/05/2023]
Abstract
Coronary artery disease is one of the leading causes of death worldwide. One of the significant causes of this disease is hypercholesterolemia which is the result of various genetic alterations that are associated with the accumulation of specific classes of lipoprotein particles in plasma. A number of drugs are used to treat hypercholesterolemia like statin, fibrate, bile acid sequestrants, niacin, ezetimibe, omega-3 fatty acids and natural extracts. It has been observed that these drugs show diverse response in different individuals. The present review explains the mechanism of action of these drugs as well as mechanism of its lesser effectiveness or resistance in some individuals. There are various identified genetic variations that are associated with diversity in the drugs response. Therefore, present study helps to understand the ethiology of drug mechanism and resistance developed against drugs used to treat hypercholesterolemia.
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Affiliation(s)
- Vishvanath Tiwari
- Department of Biochemistry, Central University of Rajasthan, Ajmer 305801, Rajasthan, India.
| | - Manoj Khokhar
- Department of Biochemistry, Central University of Rajasthan, Ajmer 305801, Rajasthan, India
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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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Xie HJ, Hai B, Wu M, Chen Q, Liu MM, Dong C, Guo ZR. Analysis on the association between PPARα/γ polymorphisms and lipoprotein(a) in a Chinese Han population. Mol Genet Genomics 2014; 289:981-7. [PMID: 24880474 DOI: 10.1007/s00438-014-0866-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 05/12/2014] [Indexed: 12/27/2022]
Abstract
Lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle, is recognized as an independent risk factor for atherosclerosis, cardiovascular diseases, and diabetic vascular diseases. Our recent studies revealed that the single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors (PPARα/δ/γ) gene are involved in the regulation of lipid storage and metabolism. In order to investigate the relationships between the SNPs of PPARα/γ gene and plasma levels of Lp(a), 644 participants were randomly selected from Chinese Han population in the present study. As the results shown, Lp(a) was significantly associated with L162V (rs1800206) in PPARα. Compared with those subjects with widetype (LL), significantly higher Lp(a) concentration was determined in the individuals with mutant (LV + VV) (mean difference: 49.07 mg/l, 95% CI 23.32-74.82 mg/l, p = 0.0002). Moreover, with generalized multifactor dimensionality reduction analysis, our present results indicated that there was a significant association between plasma Lp(a) level and gene-gene interaction among the polymorphisms rs1800206, rs135539 in PPARα and rs10865710, rs1805192, and rs4684847 in PPARγ. Therefore, our presented study indicated that PPARα/γ polymorphisms should be involved in the regulation of plasma Lp(a) in independently and/or in an interactive manner, suggesting that PPARα/γ gene may influence the risk of hypertension, cardiovascular diseases, and dyslipidemia by regulating Lp(a) level.
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Affiliation(s)
- Hui-Jian Xie
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Industrial Park District, Suzhou, 215123, Jiangsu, China
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Corton JC, Cunningham ML, Hummer BT, Lau C, Meek B, Peters JM, Popp JA, Rhomberg L, Seed J, Klaunig JE. Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol 2013; 44:1-49. [PMID: 24180432 DOI: 10.3109/10408444.2013.835784] [Citation(s) in RCA: 175] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Overall, the panel concluded that significant quantitative differences in PPARα activator-induced effects related to liver cancer formation exist between rodents and humans. On the basis of these quantitative differences, most of the workgroup felt that the rodent MOA is "not relevant to humans" with the remaining members concluding that the MOA is "unlikely to be relevant to humans". The two groups differed in their level of confidence based on perceived limitations of the quantitative and mechanistic knowledge of the species differences, which for some panel members strongly supports but cannot preclude the absence of effects under unlikely exposure scenarios.
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Smalinskiene A, Petkeviciene J, Luksiene D, Jureniene K, Klumbiene J, Lesauskaite V. Association between APOE, SCARB1, PPARα polymorphisms and serum lipids in a population of Lithuanian adults. Lipids Health Dis 2013; 12:120. [PMID: 23919842 PMCID: PMC3751123 DOI: 10.1186/1476-511x-12-120] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 07/30/2013] [Indexed: 02/07/2023] Open
Abstract
Background Dyslipidemia is one of several known risk factors for coronary heart disease, a leading cause of death in Lithuania. Blood lipid levels are influenced by multiple genetic and environmental factors. Epidemiological studies demonstrated the impact of nutrition on lipid levels within the Lithuanian population although the role of genetic factors for dyslipidemias has not yet been studied. The objective of this study was to assess the distribution of the APOE, SCARB1, PPARα genotypes in the Lithuanian adult population and to determine the relationship of these genotypes with dyslipidemia. Methods A cross-sectional health survey was carried out in a representative random sample of the Lithuanian population aged 25–64 (n=1030). A variety of single-nucleotide polymorphisms (SNPs) of the APOE (rs429358 and rs7412), SCARB1 (rs5888) and PPARα (rs1800206) genes were assessed using real-time polymerase chain reaction. Serum lipids were determined using enzymatic methods. Results/Principal findings Men and women with the APOE2 genotype had the lowest level of total and low-density lipoprotein cholesterol (LDL-C). Men with the APOE2 genotype had significantly higher levels of triglycerides (TG) than those with the APOE3 genotype. In men, the carriers of the APOE4 genotype had higher odds ratios (OR) of reduced (<1.0 mmol/L) high density lipoprotein cholesterol (HDL-C) levels versus APOE3 carriers (OR=1.98; 95% CI=1.05-3.74). The odds of having elevated (>1.7 mmol/L) TG levels was significantly lower in SCARB1 genotype CT carriers compared to men with the SCARB1 genotype CC (OR=0.50; 95% CI=0.31-0.79). In men, carriers of the PPARα genotype CG had higher OR of elevated TG levels versus carriers of PPARα genotype CC (OR=2.67; 95% CI=1.15-6.16). The odds of having high LDL-C levels were lower in women with the APOE2 genotype as compared to APOE3 genotype carriers (OR=0.35; 95% CI=0.22-0.57). Conclusions/Significance Our data suggest a gender difference in the associations between APOE, SCARB1, PPARα genotypes and lipid levels. In men, the APOE4 genotype and PPARα genotype CG were correlated with an atherogenic lipid profile while the SCARB1 genotype CT had an atheroprotective effect. In women, APOE2 carriers had the lowest odds of high LDL-C.
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Affiliation(s)
- Alina Smalinskiene
- Laboratory of Molecular Cardiology, Institute of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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de Keyser CE, Becker ML, Uitterlinden AG, Hofman A, Lous JJ, Elens L, Visser LE, van Schaik RHN, Stricker BH. Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenomics 2013; 14:1295-304. [DOI: 10.2217/pgs.13.112] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Contreras AV, Torres N, Tovar AR. PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 2013; 4:439-52. [PMID: 23858092 PMCID: PMC3941823 DOI: 10.3945/an.113.003798] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. There is evidence that genetic variants within the PPARα gene have been associated with a risk of the development of dyslipidemia and cardiovascular disease by influencing fasting and postprandial lipid concentrations; the gene variants have also been associated with an acceleration of the progression of type 2 diabetes. The interactions between genetic PPARα variants and the response to dietary factors will help to identify individuals or populations who can benefit from specific dietary recommendations. Interestingly, certain nutritional conditions, such as the prolonged consumption of a protein-restricted diet, can produce long-lasting effects on PPARα gene expression through modifications in the methylation of a specific locus surrounding the PPARα gene. Thus, this review underlines our current knowledge about the important role of PPAR-α as a mediator of the metabolic response to nutritional and environmental factors.
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Affiliation(s)
- Alejandra V. Contreras
- Faculty of Medicine, National University Autonomous of Mexico, PhD Program in Biomedical Sciences,National Institute of Genomic Medicine
| | - Nimbe Torres
- Nutrition Physiology Department, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico D.F. Mexico
| | - Armando R. Tovar
- Nutrition Physiology Department, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico D.F. Mexico,To whom correspondence should be addressed. E-mail:
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Yilmaz-Aydogan H, Kurnaz O, Kucukhuseyin O, Akadam-Teker B, Kurt O, Eronat AP, Tekeli A, Bugra Z, Ozturk O. Different effects of PPARA, PPARG and ApoE SNPs on serum lipids in patients with coronary heart disease based on the presence of diabetes. Gene 2013; 523:20-6. [DOI: 10.1016/j.gene.2013.03.136] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 03/18/2013] [Accepted: 03/28/2013] [Indexed: 02/06/2023]
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Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138:103-41. [PMID: 23333322 DOI: 10.1016/j.pharmthera.2012.12.007] [Citation(s) in RCA: 2725] [Impact Index Per Article: 227.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 12/27/2012] [Indexed: 02/06/2023]
Abstract
Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.
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Nazih H, Raffi F, Taïeb A, Reynes J, Choutet P, Cassuto JP, Ferry T, Chêne G, Leport C, Bard, for the APROCO-COPILOTE (ANRS JM. Peroxisome proliferator activating receptor alpha and gamma polymorphisms and metabolic abnormalities in HIV-infected patients receiving highly active antiretroviral therapy: the ANRS CO8 APROCO-COPILOTE study. AIDS Res Hum Retroviruses 2012; 28:393-9. [PMID: 21877956 DOI: 10.1089/aid.2010.0311] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Highly active antiretroviral therapy (HAART) is associated with fat redistribution and metabolic disorders. The present study was undertaken to evaluate the association between peroxisome proliferator activated receptor (PPAR)α and PPARγ polymorphisms, two genes involved in lipid metabolism and adipocyte differentiation, and elements of the metabolic syndrome, lipodystrophy, or carbohydrate metabolism abnormalities in patients receiving HAART. The frequency distribution of rare alleles for PPARα (L162V) and PPARγ (P12A and H449H) was compared using the chi square test in 363 HIV-1-infected patients classified according to the presence or absence of the metabolic syndrome after 48 months of follow-up on their first PI-containing regimen. The P12A rare g allele was present in 12% patients with normal glucose metabolism, 11% patients with impaired glucose tolerance or impaired fasting glucose, and 35% patients with diabetes (p=0.014). The rare g allele for L162V was present in 14% of patients free of hypertriglyceridemia and in 7% patients with hypertriglyceridemia (p=0.04). The rare g allele for L162V was found in 15% of patients free of any sign of lipodystrophy and 8% with at least one sign of lipodystrophy (p=0.04) and the rare t allele for H449H was found in 14% of patients free of any sign of lipodystrophy and 23% of patients with at least one sign of lipodystrophy (p=0.05). There was no convincing association between any polymorphism of PPARα and PPARγ and each individual component of the metabolic syndrome, except for the relationship of the P12A polymorphism with diabetes. Confirmatory studies on a larger number of individuals are needed.
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Affiliation(s)
| | | | | | - Jacques Reynes
- Service des maladies infectieuses, CHU, Montpellier, France
| | | | | | - Tristan Ferry
- Service des maladies infectieuses, CHU, Lyon, France
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Vanden Heuvel JP. Nutrigenomics and Nutrigenetics of ω3 Polyunsaturated Fatty Acids. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 108:75-112. [DOI: 10.1016/b978-0-12-398397-8.00004-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Rusyn I, Corton JC. Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate. Mutat Res 2011; 750:141-158. [PMID: 22198209 DOI: 10.1016/j.mrrev.2011.12.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 12/06/2011] [Accepted: 12/12/2011] [Indexed: 12/28/2022]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e.g., liver and testis) in rats and mice can not be ruled out and DEHP was classified as possibly carcinogenic to humans (Group 2B).
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Affiliation(s)
- Ivan Rusyn
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431, USA.
| | - J Christopher Corton
- Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA
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Garcia-Rios A, Perez-Martinez P, Delgado-Lista J, Lopez-Miranda J, Perez-Jimenez F. Nutrigenetics of the lipoprotein metabolism. Mol Nutr Food Res 2011; 56:171-83. [PMID: 22121097 DOI: 10.1002/mnfr.201100513] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 10/01/2011] [Accepted: 10/19/2011] [Indexed: 01/22/2023]
Abstract
It is well known that lipid metabolism is a cornerstone in the development of the commonest important chronic diseases worldwide, such as obesity, cardiovascular disease, or metabolic syndrome. In this regard, the area of lipid and lipoprotein metabolism is one of the areas in which the understanding of the development and progression of those metabolic disorders has been studied in greater depth. Thus, growing evidence has demonstrated that while universal recommendations might be appropriate for the general population, in this area there is great variability among individuals, related to a combination of environmental and genetic factors. Moreover, the interaction between genetic and dietary components has helped in understanding this variability. Therefore, with further study into the interaction between the most important genetic markers or single-nucleotide polymorphisms (SNPs) and diet, it may be possible to understand the variability in lipid metabolism, which could lead to an increase in the use of personalized nutrition as the best support to combat metabolic disorders. This review discusses some of the evidence in which candidate SNPs can affect the key players of lipid metabolism and how their phenotypic manifestations can be modified by dietary intake.
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Affiliation(s)
- Antonio Garcia-Rios
- Lipids and Atherosclerosis Research Unit, IMIBIC, Reina Sofia University Hospital, University of Cordoba, CIBER Fisiopatologia Obesidad y Nutricion, Instituto de Salud Carlos, Córdoba, Spain
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Effect of interaction between PPARG, PPARA and ADIPOQ gene variants and dietary fatty acids on plasma lipid profile and adiponectin concentration in a large intervention study. Proc Nutr Soc 2011; 71:141-53. [PMID: 22040870 DOI: 10.1017/s0029665111003181] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Unsaturated fatty acids are ligands of PPAR-γ, which up-regulates genes involved in fatty acid transport and TAG synthesis and the insulin-sensitising adipokine adiponectin, which activates fatty acid β-oxidation via PPAR-α action in liver. We investigated the effect of dietary fatty acid interaction with PPARG, PPARA and ADIPOQ gene variants on plasma lipid and adiponectin concentrations in the Reading Imperial Surrey Cambridge King's study, a five-centre, parallel design, randomised controlled trial of 466 subjects at increased cardiometabolic risk. After a 4-week run-in to baseline, SFA was replaced by MUFA or carbohydrate (low fat) in isoenergetic diets for 24 weeks. Habitual dietary PUFA:SFA ratio×PPARG Pro12Ala genotype interaction influenced plasma total cholesterol (P=0·02), LDL-cholesterol (P=0·002) and TAG (P=0·02) concentrations in White subjects. PPARA Val162Leu×PPARG Pro12Ala genotype interaction influenced total cholesterol (P=0·04) and TAG (P=0·03) concentrations at baseline. After high-MUFA and low-fat diets, total cholesterol and LDL-cholesterol were reduced (P<0·001) and gene×gene interaction determined LDL-cholesterol (P=0·003) and small dense LDL as a proportion of LDL (P=0·012). At baseline, ADIPOQ -10066 G/A A-allele was associated with lower serum adiponectin (n 360; P=0·03) in White subjects. After the high-MUFA diet, serum adiponectin increased in GG subjects and decreased in A-allele carriers (P=0·006 for difference). In GG, adiponectin increased with age after the high MUFA and decreased after the low-fat diet (P=0·003 for difference at 60 years). In conclusion, in Whites, high dietary PUFA:SFA would help to reduce plasma cholesterol and TAG in PPARG Ala12 carriers. In ADIPOQ -10066 GG homozygotes, a high-MUFA diet may help to increase adiponectin with advancing age.
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PPAR Genomics and Pharmacogenomics: Implications for Cardiovascular Disease. PPAR Res 2011; 2008:374549. [PMID: 18401448 PMCID: PMC2288645 DOI: 10.1155/2008/374549] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Accepted: 12/12/2007] [Indexed: 12/21/2022] Open
Abstract
The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly advancing field. This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.
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Kravchenko NA, Yarmysh NV. Role of PPARs and their isoforms in metabolic disorders related to insulin resistance and diabetes. CYTOL GENET+ 2011. [DOI: 10.3103/s0095452711030042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Cresci S, Huss JM, Beitelshees AL, Jones PG, Minton MR, Dorn GW, Kelly DP, Spertus JA, McLeod HL. A PPARα promoter variant impairs ERR-dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes. PLoS One 2010; 5:e12584. [PMID: 20838448 PMCID: PMC2933242 DOI: 10.1371/journal.pone.0012584] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Accepted: 07/19/2010] [Indexed: 11/19/2022] Open
Abstract
Activation of peroxisome proliferator-activated receptor alpha (PPARα) occurs in animal models of diabetes (DM) and is implicated in pathological responses to myocardial ischemia. Using bioinformatics, we identified a single nucleotide polymorphism (SNP) in the PPARα gene promoter (PPARA -54,642 G>A; rs135561) that altered the consensus sequence for a nuclear receptor binding site. Electrophoretic mobility shift assays showed that the domain bound two known PPARA transcriptional activators, estrogen-related receptor (ERR)-α and -γ and that PPARA G bound with greater affinity than PPARA A (>2-fold; P<0.05). Likewise, promoter-reporter analyses showed enhanced transcriptional activity for PPARA G vs. PPARA A for both ERR-α and -γ (3.1 vs.1.9-fold; P<0.05). Since PPARα activation impairs post-ischemic cardiac function in experimental models of DM, we tested whether decreased PPARA transcription in PPARA A carriers favorably impacted outcome after acute coronary ischemia in 705 patients hospitalized with acute coronary syndromes (ACS; 552 Caucasian, 106 African American). PPARA A allele frequencies were similar to non-diseased subjects. However, PPARA genotype correlated with 5-year mortality in diabetic (22.2% AA vs. 18.8% AG vs. 39.5% GG; P = 0.008), but not non-diabetic (P = 0.96) subjects (genotype by diabetes interaction P = 0.008). In the diabetic ACS subjects, PPARA A carriers had strikingly reduced all-cause mortality compared to PPARA G homozygotes, (unadjusted HR 0.44, 95% CI 0.26-0.75; P = 0.003; adjusted HR 0.48, 95% CI 0.27-0.83; P = 0.009). Consistent with previous descriptions of PPARα in experimental models and human disease, we describe a novel PPARA promoter SNP that decreases transcriptional activation of PPARA and protects against mortality in diabetic patients after ACS.
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Affiliation(s)
- Sharon Cresci
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Janice M. Huss
- City of Hope National Medical Center, Duarte, California, United States of America
| | | | - Philip G. Jones
- Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, Missouri, United States of America
| | - Matt R. Minton
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Gerald W. Dorn
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Daniel P. Kelly
- Burnham Institute for Medical Research, Orlando, Florida, United States of America
| | - John A. Spertus
- Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, Missouri, United States of America
| | - Howard L. McLeod
- University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, North Carolina, United States of America
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Rudkowska I, Caron-Dorval D, Verreault M, Couture P, Deshaies Y, Barbier O, Vohl MC. PPARalpha L162V polymorphism alters the potential of n-3 fatty acids to increase lipoprotein lipase activity. Mol Nutr Food Res 2010; 54:543-50. [PMID: 19937854 DOI: 10.1002/mnfr.200900085] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Omega-3 fatty acids (FAs) may accelerate plasma triglyceride (TG) clearance by altering lipoprotein lipase (LPL) activity. Yet, the ability of n-3 FAs to increase LPL activity is dependent on transcription factors such as peroxisome proliferator-activated receptor alpha (PPARalpha). The objective was to examine the effects of n-3 FAs on LPL activity considering the occurrence of PPARalpha L162V polymorphism. First, 14 pairs of men either L162 homozygotes or carriers of the V162 allele were supplemented with n-3 FAs. Second, transient transfections in HepG2 cells, for the L162- and V162-PPARalpha variants with the peroxisome proliferator-response element from the human LPL gene, were transactivated with n-3 FAs. In vivo results demonstrate that the LPL activity increased non-significantly by 14.4% in L162 homozygotes compared with 6.6% in carriers of the PPARalpha-V162 allele, after n-3 FA supplementation. Additionally, the L162 homozygotes tended towards an inverse correlation between LPL activities and plasma TG levels. Conversely, carriers of the V162 allele showed no such relationship. In vitro data demonstrates that transcription rates of LPL tended to be higher for the L162-PPARalpha than V162-PPARalpha after n-3 FAs activation. Overall, these results indicate that n-3 FA supplementation increases the transcription rate of LPL to a greater extent in L162-PPARalpha than V162-PPARalpha.
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Affiliation(s)
- Iwona Rudkowska
- Lipid Research Center, CHUL Research Center, Sainte-Foy, Québec, Canada
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Chen ES, Mazzotti DR, Furuya TK, Cendoroglo MS, Ramos LR, Araujo LQ, Burbano RR, Smith MDAC. Association of PPARα gene polymorphisms and lipid serum levels in a Brazilian elderly population. Exp Mol Pathol 2010; 88:197-201. [DOI: 10.1016/j.yexmp.2009.10.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 10/05/2009] [Accepted: 10/05/2009] [Indexed: 01/13/2023]
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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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Rudkowska I, Garenc C, Couture P, Vohl MC. Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARalpha L162V polymorphism. GENES AND NUTRITION 2009; 4:199-205. [PMID: 19585164 DOI: 10.1007/s12263-009-0129-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2009] [Accepted: 06/16/2009] [Indexed: 12/23/2022]
Abstract
Omega-3 fatty acids (FAs) are natural ligands of the peroxisome proliferator-activated receptor-alpha (PPARalpha), a nuclear receptor that modulates expression levels of genes involved in lipid metabolism. The L162V polymorphism of the PPARalpha gene is associated with a deteriorated metabolic profile. We postulate that subjects carrying the PPARalpha-V162 allele exhibit differences in the expression of PPARalpha and its target genes after incubation with omega-3 FAs compared with L162 homozygotes. Peripheral blood monocytes from six men carrying the PPARalpha-V162 allele paired for age and for body mass index with six L162 homozygotes were differentiated into macrophages and activated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or mixtures of EPA:DHA. Data demonstrates that gene expression levels of PPARalpha and apolipoprotein AI (APOA1) were significantly lower for carriers of the PPARalpha-V162 allele compared to L162 homozygotes after the addition of DHA and a mixture of EPA:DHA. Additionally, lipoprotein lipase (LPL) gene expression displayed a tendency to be lower in the PPARalpha L162V polymorphism subgroup after the addition of a mixture of EPA:DHA. Consequently, individuals carrying the PPARalpha-V162 allele may demonstrate inferior improvements in their lipid profile due to alterations in gene expression rates in response to omega-3 FA supplementation.
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Affiliation(s)
- Iwona Rudkowska
- Lipid Research Center, CHUL Research Center, The Nutraceuticals and Functional Foods Institute (INAF), Quebec, Canada
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Turner ST, Fornage M, Jack CR, Mosley TH, Knopman DS, Kardia SLR, Boerwinkle E, de Andrade M. Genomic susceptibility Loci for brain atrophy, ventricular volume, and leukoaraiosis in hypertensive sibships. ARCHIVES OF NEUROLOGY 2009; 66:847-57. [PMID: 19597086 PMCID: PMC2828902 DOI: 10.1001/archneurol.2009.110] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE To localize susceptibility genes for alterations in brain structure associated with risk of stroke and dementia. We conducted genomewide linkage analyses for magnetic resonance imaging (MRI) measures of brain atrophy, ventricular, and subcortical white matter hyperintensity (leukoaraiosis) in 689 non-Hispanic white (673 sibling pairs; median age, 61 years) and 544 non-Hispanic black participants (503 sibling pairs; median age, 64 years) from sibships with at least 2 members with essential hypertension. DESIGN, SETTING, AND PATIENTS We determined brain, ventricular, and leukoaraiosis volumes from axial fluid-attenuated inversion recovery MRI; we calculated brain atrophy as the difference between total intracranial and brain volumes. Microsatellite markers (n = 451) distributed across the 22 autosomes were genotyped, and we used variance components methods to estimate heritability and assess evidence of genetic linkage for each MRI measure. MAIN OUTCOME MEASURES Brain atrophy ventricular volume, and leukoaraiosis determined from fluid-attenuated inversion recovery MRI. RESULTS In both races, the heritability of each MRI measure was statistically greater than 0 (P < .001), ranging in magnitude from 0.42 (for ventricular volume in blacks) to 0.69 (for brain atrophy in blacks). Based on multipoint logarithm of odds scores (MLS), the strongest evidence of genetic linkage was observed for brain atrophy on chromosomes 1 (MLS, 3.49 at 161 cM; P < .001) and 17 (MLS, 3.08 at 18 cM; P < .001) in whites; for ventricular volume on chromosome 12 (MLS, 3.67 at 49 cM; P < .001) in blacks and chromosome 10 (MLS, 2.47 at 110 cM; P < .001) in whites; and for leukoaraiosis on chromosome 11 (MLS, 2.21 at 118 cM; P < .001) in whites and chromosome 22 (MLS, 2.02 at 36 cM; P = .001) in blacks. CONCLUSIONS The MRI measures of structural brain injury are heritable in non-Hispanic black and white sibships ascertained through hypertensive sibling pairs. The susceptibility loci for brain atrophy, ventricular volume, and leukoaraiosis identified by linkage analyses differ among MRI measures and between races.
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Affiliation(s)
- Stephen T Turner
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
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Pishva H, Mahboob SA, Mehdipour P, Eshraghian MR, Mohammadi-Asl J, Hosseini S, Rahmany M. Association between the FABP2 Ala54Thr, PPARα Leu162/Val, and PPARα intron7 polymorphisms and blood lipids ApoB and ApoCIII in hypertriglyceridemic subjects in Tehran. J Clin Lipidol 2009; 3:187-194. [PMID: 21291813 DOI: 10.1016/j.jacl.2009.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 04/07/2009] [Accepted: 04/13/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND The alanine to threonine substitution at codon 54 in the FABP2 gene and PPARα Val162 allele have been associated with hypertriglyceridemia. OBJECTIVE We sought to determine the prevalence of the Ala54Thr polymorphism of fatty acid binding protein (FABP) 2 gene and the Leu162/Val in exon 5 and G/C in intron7 polymorphism of peroxisome proliferator-activated receptor alpha (PPARα) gene in hypertriglyceridemic patients and their associations with blood lipid concentrations. METHODS A total of 170 hypertriglyceridemic subjects were enrolled and genotyped for Ala54Thr, Leu162Val, and intron 7 polymorphism by the use of a polymerase chain reaction-restriction fragment length polymorphism method. Fasting blood triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein (Apo)B, and ApoCIII also were determined. RESULTS We found frequency of 81.2% for the Thr54 polymorphism among hypertriglyceridemic subjects. Positive associations were observed between this polymorphism and greater blood triglyceride, very low-density lipoprotein, and ApoCIII levels and lower blood high-density lipoprotein cholesterol concentration both in men and women. However, no association was found between the Thr54 polymorphism and TC, low-density lipoprotein cholesterol, ApoB, and body mass index. Frequency of the Leu162Val polymorphism was 21.8%. The Leu162Val polymorphism was not associated with lipid and lipoprotein concentrations in hypertriglyceridemic subjects (both in men and women). The frequency of intron7 polymorphism was 55.3% in subjects studied and, except for body mass index and TC, no association was found between the intron7 allele and blood lipids ApoB, and ApoCIII. CONCLUSION Frequency of the Thr54 polymorphism is high in hypertriglyceridemic subjects, and the presence of this allele may increase some blood lipid and lipoprotein concentrations. In addition, the frequency of intron7 polymorphism may be greater than Leu162Val in hypertriglyceridemic patients.
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Affiliation(s)
- Hamideh Pishva
- Department of Nutrition and Biochemistry, School of Public Health and Institute of Public Research, Tehran University of Medical Sciences, Tehran, Iran
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