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Reza-López SA, González-Gurrola S, Morales-Morales OO, Moreno-González JG, Rivas-Gómez AM, González-Rodríguez E, Moreno-Brito V, Licón-Trillo A, Leal-Berumen I. Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-β/δ Polymorphisms. Biomolecules 2023; 13:1791. [PMID: 38136661 PMCID: PMC10741495 DOI: 10.3390/biom13121791] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. OBJECTIVE To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). MATERIALS AND METHODS We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-β/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. RESULTS minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-β/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. CONCLUSIONS PPAR-γ2 rs1801282 and PPAR-β/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.
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Affiliation(s)
- Sandra A. Reza-López
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Susana González-Gurrola
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Oscar O. Morales-Morales
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Janette G. Moreno-González
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Ana M. Rivas-Gómez
- Instituto Mexicano del Seguro Social UMF 33, Avenida Melchor Ocampo y Arroyo de los Perros S/N, Col. El Palomar, Chihuahua 31204, CP, Mexico; (S.G.-G.); or (A.M.R.-G.)
| | - Everardo González-Rodríguez
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Verónica Moreno-Brito
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Angel Licón-Trillo
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
| | - Irene Leal-Berumen
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Campus II. Circuito Universitario S/N, Chihuahua 31109, CP, Mexico; (S.A.R.-L.); (O.O.M.-M.); (J.G.M.-G.); (E.G.-R.); (V.M.-B.); (A.L.-T.)
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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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Ke T, Dorajoo R, Han Y, Khor CC, van Dam RM, Yuan JM, Koh WP, Liu J, Teo YY, Goh DYT, Tai ES, Wong TY, Cheng CY, Friedlander Y, Heng CK. Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population. Ann Hum Genet 2016; 80:282-93. [PMID: 27530449 DOI: 10.1111/ahg.12164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 11/30/2022]
Abstract
Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) < 0.2) were selected. The effect of interactions between PPAR SNPs and those across the genome on HDL-C was tested using linear regression models. One statistically significant interaction influencing HDL-C was detected between PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, β = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population.
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Affiliation(s)
- Tingjing Ke
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Yi Han
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.,Duke-NUS Graduate Medical School, Singapore
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
| | - Yik Ying Teo
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.,Department of Statistics and Applied Probability, National University of Singapore, Singapore
| | - Daniel Y T Goh
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
| | - E Shyong Tai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Tien Yin Wong
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore.,Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ching-Yu Cheng
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore.,Academic Medicine Research Institute, Duke-NUS Graduate Medical School, National University of Singapore, Singapore
| | - Yechiel Friedlander
- School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore and Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore
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Tang L, Lü Q, Cao H, Yang Q, Tong N. PPARD rs2016520 polymorphism is associated with metabolic traits in a large population of Chinese adults. Gene 2016; 585:191-195. [PMID: 26915488 DOI: 10.1016/j.gene.2016.02.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 12/12/2015] [Accepted: 02/21/2016] [Indexed: 12/15/2022]
Abstract
AIMS Polymorphism of rs2016520 in gene PPARD has been associated with lipid metabolism, obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). We aimed to study the association of rs2016520 with common metabolic traits in a large population of Han Chinese adults. METHODS The polymorphism was genotyped in 1409 subjects using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent standard clinical examination and a 75g oral glucose tolerance test (OGTT); associations between the polymorphism and metabolic traits and indices of insulin resistance and insulin sensitivity were analyzed. RESULTS There was no significant difference in genotypes between the normal glucose tolerance (NGT) and the prediabetes group (χ(2)=3.17, P=0.2), except a nominal difference of allele frequency (χ(2)=3.07, P=0.07). The G carrier presented lower fasting plasma glucose (FPG, P=0.03), lower 2h plasma glucose (Pdom=0.04) and lower fasting insulin (P=0.02), lower systolic blood pressure (SBP, P=0.03), lower HOMA-IR (P=0.02) and higher QUICKI (P=0.01). Moreover, rs2016520 polymorphism was associated with FPG (β=-0.09, P=0.05), it was also associated with indices of insulin resistance (HOMA-IR, β=-0.06, Pdom=0.02; fasting insulin, β=-0.04, P=0.02) and indices of insulin sensitivity (QUICKI, β=-0.01, P=0.004). In addition, we observed that the allele G was also associated with lower SBP (β=-1.29, P=0.04) and diastolic blood pressure (DBP, β=-0.09, P=0.01). However, the minor allele G was not associated with risk of metabolic disorders including prediabetes, overweight, hypertension and metabolic syndrome. CONCLUSIONS Polymorphism of rs2016520 in gene PPARD was associated with benign metabolic traits in a large cohort of Chinese adults. The G allele may confer protection from type 2 diabetes and hypertension in Han Chinese.
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Affiliation(s)
- Lizhi Tang
- Division of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qingguo Lü
- Division of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hongyi Cao
- Division of Endocrinology and Metabolism, Chengdu Fifth People's Hospital, Chengdu, Sichuan, China
| | - Qiu Yang
- Division of Endocrinology and Metabolism, Chengdu Fifth People's Hospital, Chengdu, Sichuan, China
| | - Nanwei Tong
- Division of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
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Dong C, Zhou H, Shen C, Yu LG, Ding Y, Zhang YH, Guo ZR. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome. World J Diabetes 2015; 6:654-661. [PMID: 25987964 PMCID: PMC4434087 DOI: 10.4239/wjd.v6.i4.654] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/27/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.
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Ehrenborg E, Skogsberg J. Peroxisome proliferator-activated receptor delta and cardiovascular disease. Atherosclerosis 2013; 231:95-106. [PMID: 24125418 DOI: 10.1016/j.atherosclerosis.2013.08.027] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 08/16/2013] [Accepted: 08/27/2013] [Indexed: 12/20/2022]
Abstract
Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD). Specific human PPARD gene variants show no clear association with CVD but interactions between variants and lifestyle factors might influence disease risk. During recent years, development of specific and potent PPARD agonists has also made it possible to study the effects of PPARD activation in humans. PPARD agonists seem to exert beneficial effects on dyslipidemia and insulin-resistant syndromes but safety issues have been raised due to the role that PPARD plays in cell proliferation. Thus, large long term outcome as well as detailed safety and tolerability studies are needed to evaluate whether PPARD agonists could be used to treat CVD in humans.
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Affiliation(s)
- Ewa Ehrenborg
- Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
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Effect of genetic polymorphism +294T/C in peroxisome proliferator-activated receptor delta on the risk of ischemic stroke in a Tunisian population. J Mol Neurosci 2013; 50:360-7. [PMID: 23512374 DOI: 10.1007/s12031-013-9997-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Accepted: 03/05/2013] [Indexed: 12/14/2022]
Abstract
PPARδ +294T/C polymorphism was investigated in diabetics, in normolipidemic healthy controls, in dyslipidemic and nondyslipidemic coronary artery disease patients but never in ischemic stroke patients. The aim of this study was to explore, for the first time, the relationship between the genetic polymorphism of PPARδ and the risk of ischemic stroke among patients with diabetes. The study group consisted of 196 patients with ischemic stroke and 192 controls. Plasma concentrations of total cholesterol, triglycerides, low-, and high-density lipoprotein did not differ significantly between subjects carrying the TT genotype and those carrying the CC/TC genotype in both ischemic stroke patients (with or without diabetes) and control groups. The +294C allele (CC + CT genotypes) as compared with TT genotypes was found to be higher in total ischemic stroke patients than in controls. On the other hand, no interaction between diabetes and PPAR +294T/C polymorphism on the risk of ischemic stroke was found (p = 0.089). The PPARδ +294T/C polymorphism was associated with the risk of ischemic stroke in Tunisian subjects. This polymorphism has no influence on plasma lipoprotein concentrations and body mass index either in healthy subjects or in ischemic stroke patients with or without diabetes both in males and females.
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