Peroxisome Proliferator-activated Receptor-gamma Coactivator-1alpha Gene Research Articles

PGC-1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age-related macular degeneration.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.

Молекулярно-генетический анализ генов ADRB2, NOS3 и PPARGC1A у единоборцев города Перми

The study of genetic predisposition to certain types of sports activities will make it possible to sci-entifically select the most promising athletes and adjust their training process, since these data influence the formation of the physical qualities of athletes. The purpose of this study is to identify the relationship between pol-ymorphic variants of the ADRB2 (Adrenoceptor Beta 2), NOS3 (Nitric Oxide Synthase 3) и PPARGC1A (Peroxi-some Proliferator-Activated Receptor Gamma Coactivator 1-Alpha) genes associated with endurance in judo and freestyle wrestling athletes with different sports qualifications. The sample for the study included 50 ath-letes, of which 27 were athletes involved in judo at the «Vityaz» sports school, and 23 athletes involved in free-style wrestling at the «Planeta» sports and health club in the city of Perm. Depending on their sporting success, the combatants were distributed into Group I with high qualifications and into Group II with low qualifications. In 50 martial artists aged 10 to 16 years, laboratory research was carried out using real-time polymerase chain reaction (PCR-RT) and polymorphisms of three genes were identified: G/T polymorphism of the NOS3 gene (rs1799983), G/A polymorphism of the PPARGC1A gene (rs8192678) and A/G polymorphism of the ADRB2 gene (rs1042713). An analysis of the relationship between allelic variants of genes in martial artists and their sports qualifications was carried out. An analysis of the relationship between allelic variants of genes in martial artists and their sports qualifications was carried out; significant differences were established between Group I and Group II for genotype A/A (Fexp 2.98>1.96 at p=0.05) and genotype G/G (Fexp 2.60>1.96 at p=0.05) of the ADRB2 gene, and also for the G/A genotype of the PPARGC1A gene (Fexp 2.43>1.96 at p=0.05). The frequency of occurrence of TGS, calculated for the physical quality “endurance”, based on the polymorphism of the ADRB2, NOS3 and PPARGC1A genes in 50 martial artists, ranged from 33 to 100. Combatants with the greatest TGS are highly qualified. The relationship between the two samples (Group I with high qualifications and Group II with low qualifications) and TGS, established based on the analysis of polymorphic positions of three genes (ADRB2, NOS3 and PPARGC1A) is statistically insignificant.

Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease: An Individual-Level Meta-Analysis.

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator–activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98–1.05 and rs7672915, HR: 0.97, 95% CI 0.94–1.00; rs3755863, HR: 1.02, 95% CI 0.99–1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases.

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism's genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.

Association study of rs7799039, rs1137101 and rs8192678 gene variants with disease susceptibility/severity and corresponding LEP, LEPR and PGC1A gene expression in multiple sclerosis

Leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1A) are involved in the pathogenesis of multiple sclerosis (MS) by affecting the inflammatory response and reactive oxygen species production. LEP rs7799039 and LEPR rs1137101 genetic variants modify the serum LEP levels and PGC1A rs8192678 alters the PGC1A activity. The study objective was to explore the associations of these variants with susceptibility to MS, disease course/clinical parameters and also with peripheral blood mononuclear cell expression of the target genes and plasma LEP concentrations, in the study subjects. The study groups included 528 patients with MS and 429 controls. TaqMan® assays were used for genotyping and gene expression quantification. The Chi-square, parametric and nonparametric tests and simple/multiple logistic regression were performed for the statistical analysis of data. A multiple logistic regression model including all three investigated variants, applied to patients (RRMS+SPMS) and controls, showed that PGC1A rs8192678 minor allele had an increased risk for the occurrence of disease, with OR (95%CI)=1,32 (1,01-1,73), P=0,04. Between-effect of gender and LEPR variant on the multiple sclerosis severity score (MSSS) was identified (P=0,005). In male patients (relapsing-remitting and secondary progressive), LEPR minor allele carriers had increased MSSS (GG+AG vs AA, median (minimum-maximum)=5,38 (0,64-9,88) vs 4,27 (0,78-9,63); P=0,01, Padj=0,03). In relapsing-remitting patients LEP rs7799039 affected the LEP gene expression (P=0,006; Padj=0,04). The current findings implicate an impact of investigated genetic variants on the pathogenesis of MS.

A novel 17 bp InDel polymorphism within the PPARGC1A gene is significantly associated with growth traits in sheep

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) is a member of transcriptional coactivator of the peroxisome proliferator-activated receptor. It is involved in lipid metabolism, energy metabolism, adipocyte differentiation and regulation of mitochondrial biogenesis. Therefore, the genetic variation of PPARGC1A gene will be of great value. The purposes of this study were to detect novel InDels within the PPARGC1A gene and analyze the effects of genetic polymorphisms on growth traits. We detected a novel 17 bp insertion polymorphism within the eleventh intron of the sheep PPARGC1A gene. Experimental results revealed that the InDel (insertion/deletion) genotypes distribution of the seven breeds of sheep was significant differences, of which three genotypes were detected. After correlation analysis, there were many significant phenotypic differences between the body size traits of the three genotypes. Interestingly, the dominant genotype was different in body weight both in STHS sheep and HS sheep. In summary, the 17 bp insertion polymorphism within the PPARGC1A gene had a great influence on the growth traits of sheep, which may provide a potential theoretical basis for marker-assisted selection in sheep genetic breeding.

Expression of LEP, LEPR and PGC1A genes is altered in peripheral blood mononuclear cells of patients with relapsing-remitting multiple sclerosis

Leptin (LEP) may contribute to the pathogenesis of multiple sclerosis (MS) by its immunomodulatory, proinflammatory and prooxidant effects. Therefore, plasma LEP levels and mRNA expression of five genes related to the LEP signaling pathway (LEP, LEP receptor (LEPR), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1A), superoxide dismutase 2, tumor necrosis factor-alpha) were investigated in relapsing-remitting MS. In patients (N = 64), compared to healthy subjects (N = 62), relative LEP mRNA levels were significantly increased (p = 0,01), while LEPR and PGC1A mRNA levels were decreased (p = 0,001 and p = 0,04, respectively). Significant positive correlation was observed between LEPR mRNA levels and clinical parameters of MS progression (EDSS, MSSS).

Analysis of Single Nucleotide Polymorphisms of STK32B, PPARGC1A and CTNNA3 Gene With Sporadic Parkinson's Disease Susceptibility in Chinese Han Population.

Recently, five novel single nucleotide polymorphisms (SNPs), rs10937625 in STK32B (serine/threonine kinase 32B), rs17590046 in PPARGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and rs12764057, rs10822974, and rs7903491 in CTNNA3 (catenin alpha 3), were found to be associated with increased risk of essential tremor (ET) in a genome-wide association study (GWAS)in individuals of Caucasian ancestry. Considering the overlap between ET and Parkinson's disease (PD) in pathological features and clinical manifestations, a case-control study comprising 546 PD patients and 550 control subjects was carried out to examine whether the same variants were also associated with PD in Chinese Han population. However, the above variants did not show an association with PD. Our results suggested that these variants do not play a major role in PD in the Chinese population, Actually, the clinical overlap between PD and ET is under debate. In our Chinese Han cohort, we did not verify potential genetic pleiotropy between two diseases, which may indicated that etiology and pathobiology of PD and ET are distinct. Thus, a more comprehensive study such as a multi-center study may be helpful to evaluate the relationship between the five new susceptible loci and PD in Chinese Han population in the future.

Анализ ассоциаций полиморфизмов G1444A гена PPARGC1A и A1166C гена AGTR1 с преморбидными особенностями личности при шизофрении

Background: it is assumed that a number of metabolic changes and initial psychopathological anomalies of patients with endogenous psychoses are formed long before the manifestation of the disease, is associated with a hereditary, genetic component and can be reflected in the constitutional features of the patients already in the premorbid period of the disease and be a promising method for early recognition. Previously, the participation of PPARGC1A (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and AGTR1(Angiotensin II Receptor Type 1) genes in the formation of both metabolic and morphofunctional, neurodegenerative, cognitive and other mental disorders was repeatedly demonstrated. The aim of study was to study the frequency distribution of the polymorphic markers G1444A of the PPARGC1A gene (rs8192678) and A1166C of the AGTR1 gene (rs5186) in patients with schizophrenia (ICD-10: F20, F25), depending on their afliation to the subgroups isolated according to the severity of premorbid personality anomalies: accentuated, with personality disorder (or psychopathy), with pseudopsychopathy. Material: a sample of patients was formed of in-patients (all men) of clinical unit of FSBSI «Mental health research centre». The control group consisted of 290 healthy men. DNA for the study was isolated from the venous blood of the recipients. Methods: genotyping was performed by standard PCR with further analysis of MspI restriction fragments (for rs8192678) and DstDEI fragments (for rs5186). Statistical processing of data was carried out using the program Statistica 6.0. Results: the association of studied markers with the severity of premorbid personality anomalies in patients was revealed. Thus, in the subgroup of patients with personality disorder, an increase in the frequency of the CC genotype (A1166C of the AGTR1 gene) and a decrease in the frequency of the GG genotype (G1444A of the PPARGC1A gene) compared to other subgroups; and in the subgroup of patients with pseudopsychopathy — a decrease in the frequency of the genotype CC (A1166C gene AGTR1) and an increase in the frequency of the genotype GG (G1444A gene PPARGS1A). This may indicate the possible involvement of these genes in the formation of psychopathological and biological changes in patients with schizophrenia at the stages preceding the manifestation of the disease.

Expression of Mitochondria-Associated Genes (PPARGC1A, NRF-1, BCL-2 and BAX) in Follicular Development and Atresia of Goat Ovaries.

Most follicles undergo atresia during the developmental process. Follicular atresia is predominantly regulated by apoptosis of granulosa cells, but the mechanism underlying apoptosis via the mitochondria-dependent apoptotic pathway is unclear. We aimed to investigate whether the mitochondria-associated genes peroxisome proliferator-activated receptor-gamma, coactivator1-alpha (PPARGC1A), nuclear respiratory factor-1 (NRF-1), B-cell CLL/lymphoma 2 (BCL-2) and BCL2-associated X protein (BAX) played a role in follicular atresia through this pathway. The four mitochondria-associated proteins (PGC-1α, which are encoded by the PPARGC1A gene, NRF-1, BCL-2 and BAX) mainly expressed in granulosa cells. The mRNA and protein levels of PPARGC1A/PGC-1α and NRF-1 in granulosa cells increased with the follicular development. These results showed that these genes may play a role in the regulation of the follicular development. In addition, compared with healthy follicles, the granulosa cell in atretic follicles had a reduced expression of NRF-1, increased BAX expression and increased ratio of BAX to BCL-2 expression. These results suggested that changes of the mitochondria-associated gene expression patterns in granulosa cells may lead to follicular atresia during goat follicle development.

Single nucleotide polymorphism scanning and expression of the pig PPARGC1A gene in different breeds.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) is a candidate gene for lean meat production because it plays a key role in lipid metabolism. In this study, SNPs within the porcine PPARGC1A gene were investigated using PCR-sequencing and PCR-RFLP. Quantitative real-time PCR and Western blot were then used to analyze mRNA and protein expression in longissimus dorsi muscle (LM), liver, and backfat tissues of Dianna small-ear pigs (DSP, n = 6), Tibetan pigs (TP, n = 6), and large white pigs (LW, n = 6). Five novel SNPs (g.-1269A>G in the 5'-upstream regulatory region; g.190C>T, g.218C>A and g.234C>A in exon 8; and g.20C>T in intron 10) and three previously identified SNPs (g.417A>T in exon 8; g.56C>A in exon 9; and g.34G>A in intron 9) were found. Of these, only two, g.-1269A>G and g.234C>A, had three different genotypes in the three breeds (DSP, n = 63; TP, n = 51; and LW, n = 52). Expression was highest in LM, modest in the liver, and minimal in backfat. In LM tissue, LW had higher mRNA and protein levels than DSP and TP (P < 0.05), and there was a negative correlation between gene expression and intramuscular fat (IMF) content. LW had numerically higher expression in liver and backfat tissues than DSP and TP, and the differences in protein levels were significant (P < 0.05 in liver, P < 0.01 in backfat). In conclusion, PPARGC1A may play a key role in down-regulating lipid deposition, and the SNPs with differential genotype distribution among the three pig breeds may be related to gene expression and fat deposition.

Association study of common polymorphisms in MSRA, TFAP2B, MC4R, NRXN3, PPARGC1A, TMEM18, SEC16B, HOXB5 and OLFM4 genes with obesity-related traits among Portuguese children

At least 52 genetic loci were associated with obesity-related traits. However, little is known about the genetic basis of obesity among children. This study aims to test whether 10 polymorphisms in obesity-related genes methionine sulfoxide reductase A (MSRA), transcription factor AP-2 beta (TFAP2B), melanocortin 4 receptor (MC4R), neurexin 3 (NRXN3), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), transmembrane protein 18 (TMEM18), homolog of S. cerevisiae Sec16 (SEC16B), homeobox B5 (HOXB5) and olfactomedin 4 (OLFM4) are associated with the risk of obesity in Portuguese children. A total of 730 children aging from 6 to 12 years old, recruited randomly from public schools in Portugal, were analysed. Anthropometric measurements were obtained and children were classified into three phenotypic groups, normal weight (n=256), overweight (n=320) and obese (n=154), according to the International Obesity Task Force cutoffs. Polymorphisms were genotyped by allelic discrimination TaqMan assays. The MC4R rs12970134 polymorphism was nominally associated with body mass index (BMI) (P=0.035), BMI Z-score (P=0.043) and waist circumference (P=0.020), and borderline associated with weight (P=0.053). Near nominal associations were also found for the PPARGC1A rs8192678 polymorphism with weight (P=0.061), and for the MSRA rs545854 polymorphism with BMI (P=0.055) and BMI Z-score (P=0.056). Furthermore, logistic regression showed that MC4R rs12970134 and TFAP2B rs987237 were nominally, respectively, associated (P=0.029) and borderline associated (P=0.056) with the obese phenotype. This study highlighted the possible association of MC4R, PPARGC1A, MSRA and TFAP2B polymorphisms with several obesity-related traits in a sample of Portuguese children. The two significant associated TFAP2B rs987237 and MC4R rs12970134 polymorphisms showed an opposite direction of effect to that in the original reports.

Genotype and allele frequencies of polymorphisms in ABCG2, PPARGC1A and OLR1 genes in indigenous cattle breeds in Turkey

Abstract This study was carried out to determine polymorphisms of four genes in South Anatolian Red (SAR) and East Anatolian Red (EAR) indigenous cattle breeds in Turkey. Single nucleotide polymorphisms (SNPs) monitored in this study are Y581S in ATP binding cassette sub family G member 2 (ABCG2) gene, c.1892T&gt;C and c.3359A&gt;C in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene and g.8232C&gt;A in oxidized low-density lipoprotein receptor 1 (OLR1) gene. The frequency of the ancestral allele A of the ABCG2 gene Y581S polymorphism was found to be very high (SAR: 0.63; EAR: 0.64) in both cattle breeds. The CC genotypes of PPARGC1A gene c.1892T&gt;C (SAR: 0.65; EAR: 0.80) and OLR1 gene g.8232C&gt;A polymorphisms (SAR: 0.82; EAR: 0.86), which are associated with high milk fat percentage, had higher frequencies than those of the other genotypes. In conclusion, we might suggest that the allele distribution of the ABCG2 gene Y581S polymorphism can be the evidence indicating autosomal gene flow from zebu cattle to SAR and EAR cattle breeds.

Prevalence of Gly482Ser polymorphism of PPARGC1A in Cuban Americans

Type 2 Diabetes (T2D) has grown to be a major public health issue worldwide. The fundamental clinical characteristic of T2D is high blood glucose levels which may be caused by anomalies in one or more different molecular pathways regulated by certain genes. The Gly482Ser polymorphism in human peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PPARGC1A) has been associated with T2D. We genotyped Gly482Ser polymorphism in the PPARGC1A gene from 315 Cuban Americans (164 without T2D / 151 with T2D) using ABI TaqMan assays. Descriptive statistical analysis was performed using SPSS software. The genotype distribution for rs8192678 (Gly482Ser) polymorphism was found to be 0.42 for Gly/Gly, 0.47 for Gly/Ser and 0.10 for Ser/Ser with T2D and 0.47, 0.41 and 0.11 for Gly/Gly, Gly/Ser and Ser/Ser respectively without T2D. The findings in individuals without T2D demonstrate presence of homozygous genotype Gly/Gly to be highest. However, the prevalence of heterozygous genotype Gly/Ser was found to be relatively higher in individuals with T2D than without T2D. The clinical importance of the results has to be established in further studies. Funding was provided by an NIH grant.

Does DNA Methylation of PPARGC1A Influence Insulin Action in First Degree Relatives of Patients with Type 2 Diabetes?

Epigenetics may play a role in the pathophysiology of type 2 diabetes (T2D), and increased DNA methylation of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) has been reported in muscle and pancreatic islets from T2D patients and in muscle from individuals at risk of T2D. This study aimed to investigate DNA promoter methylation and gene expression of PPARGC1A in skeletal muscle from first degree relatives (FDR) of T2D patients, and to determine the association with insulin action as well as the influence of family relation. We included 124 Danish FDR of T2D patients from 46 different families. Skeletal muscle biopsies were excised from vastus lateralis and insulin action was assessed by oral glucose tolerance tests. DNA methylation and mRNA expression levels were measured using bisulfite sequencing and quantitative real-time PCR, respectively. The average PPARGC1A methylation at four CpG sites situated 867-624 bp from the transcription start was associated with whole-body insulin sensitivity in a paradoxical positive manner (β = 0.12, P = 0.03), supported by a borderline significant inverse correlation with fasting insulin levels (β = −0.88, P = 0.06). Excluding individuals with prediabetes and overt diabetes did not affect the overall result. DNA promoter methylation was not associated with PPARGC1A gene expression. The familiality estimate of PPARGC1A gene expression was high (h2 = 79±27% (h2±SE), P = 0.002), suggesting genetic regulation to play a role. No significant effect of familiality on DNA methylation was found. Taken together, increased DNA methylation of the PPARGC1A promoter is unlikely to play a major causal role for the development of insulin resistance in FDR of patients with T2D.

Association of peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PPARGC1A) gene polymorphisms and type 2 diabetes mellitus: a meta‐analysis

The association between peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) polymorphisms and type 2 diabetes mellitus (T2DM) has been investigated in several studies, but these studies yielded contradictory results. We conducted a meta-analysis to assess the association between three polymorphisms (Gly482Ser, Thr394Thr and Thr612Met) in PPARGC1A and T2DM. A literature-based search was conducted to collect data. The additive model was chosen to investigate the association between the three polymorphisms and T2DM. The random effects model was used if there was heterogeneity between studies. In addition, subgroup meta-analyses were made according to the ethnic groups. Twenty-three studies were enrolled in this meta-analysis (7539 cases and 9562 controls for Gly482Ser, 1818 cases and 2376 controls for Thr394Thr, 2042 cases and 1289 controls for Thr612Met). In the combined analysis of all eligible studies, a significant association was found between Gly482Ser, Thr394Thr and T2DM with pooled odds ratios 1.19 [95% confidence interval (CI) 1.05-1.34] and 1.33 (95% CI 1.04-1.70), respectively, but great heterogeneity was found between studies. In the subgroup meta-analyses, we found that Gly482Ser and Thr394Thr polymorphisms were associated with the risk of T2DM, and the pooled odds ratios were 1.66 (95% CI 1.28-2.15) and 1.72 (95% CI 1.45-2.03), respectively, in the Indian population; no significant evidence was found in the Caucasian and East Asian populations. This meta-analysis indicated that Gly482Ser and Thr394Thr polymorphisms of PPARGC1A gene were significantly associated with the risk of T2DM, especially in the Indian population. No relationship was found between the Thr612Met and risk of T2DM.

Rapid and cost effective genotyping method for polymorphisms in PPARG, PPARGC1 and TCF7L2 genes

Polymorphisms (rs1801282, rs8192678, rs7903146) of peroxisome proliferator-activated receptor gamma ( PPARG), peroxisome proliferator-activated receptor gamma coactivator-1 alpha ( PPARGC1A) and transcription factor 7-like 2 ( TCF7L2) have recently been associated with different diseases, mainly type 2 diabetes. An assay using unlabeled probes and the LightCycler or Rotor-Gene instruments was developed for genotyping of these three polymorphisms. Asymmetric polymerase chain reaction was used, followed by melting analysis of the unlabeled probe/ssDNA amplicon duplex. Samples with the target genotypes were accurately detected and easily distinguishable. Thus, genotyping using unlabeled probes is a rapid, accurate and cost effective closed-tube method. These assays demonstrated 100% specificity and sensitivity for the identification of selected polymorphisms in PPARG, PPARGC1A and TCF7L2 genes.

The Association of Bovine PPARGC1A and OPN Genes with Milk Composition in Two Independent Holstein Cattle Populations

Many studies have reported quantitative trait loci on chromosome 6 that affect milk production traits in dairy cattle. Osteopontin (OPN) and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PPARGC1A) are located in the middle of chromosome 6 about 6 Mb apart, which is approximately 12 cM. The objective of this study was to investigate the association of OPN and PPARGC1A variants with milk production traits in 2 independent Holstein cattle populations: the University of Wisconsin (UW) daughter design and the Cooperative Dairy DNA Repository (CDDR) granddaughter design resource populations. For OPN, 891 cows from the UW resource population were genotyped for the C/T polymorphism reported previously in the CDDR population. Additive effects were significant for fat percentage, protein percentage, and fat yield in the UW resource population. These results are consistent with previous studies that have shown significant association of OPN variants with milk composition traits. The association between PPARC1A variants was investigated in UW and CDDR resource populations using 2 single nucleotide polymorphisms. For the UW resource population, additive effects were significantly increased for protein percentage and decreased for milk yield. Dominance effects were not significant for any of the examined traits. For the CDDR population, PPARGC1A was associated with a significant increase in milk protein percentage and in SCS. Thus, in UW and CDDR populations, PPARGC1A was associated with a significant increase in milk protein percentage in contrast to association results previously reported for the German Holstein population.

Peroxisome Proliferator-Activated REceptor γ Coactivator-1α Gene Variations Are Not Associated With Gestational Diabetes Mellitus

Epidemiologic, pathophysiologic, and genetic data suggest a close link between gestational diabetes mellitus (GDM) and type 2 diabetes. Previous studies yielded controversial results on the impact of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1) gene variations on the development of type 2 diabetes mellitus. Therefore, we examined two common single nucleotide polymorphisms (SNP) of this gene in women with GDM. We assessed a total of 875 women by oral glucose tolerance testing (OGTT). Two hundred women of this population, 100 patients with an abnormal OGTT and 100 normal controls, were randomly selected. DNA samples isolated from the blood of the control and study groups were analyzed with respect to the SNP Gly482Ser and Thr394Thr of the PGC-1 gene using polymerase chain reaction (PCR) amplification and restriction analysis. Furthermore, a potential interaction between the Gly482Ser and the Thr394Thr variant on the risk of GDM was investigated. Women with GDM were significantly older (32.2 +/-5.5 years vs 29.7 +/- 6.1 years; P = .005), had higher body mass indices (BMI; 28.0 +/- 7.1 kg/m2 vs 25.0 +/- 5.7 kg/m2; P = .002) and displayed higher hemoglobin A1c (HbA1c) values (5.6 +/- 0.9 vs 4.9 +/- 0.5; P <.001). There was no significant difference between the allele distribution of the two polymorphisms in women with and without GDM. No significant associations between the two polymorphisms and BMI or OGTT values were observed. When the different haplotype combinations of the two loci were analyzed for the risk of GDM, no significant association could be found. Based on our data, the Gly482Ser and the Thr394Thr polymorphisms of the PGC-1 gene are not associated with the development of GDM.

Effect of polymorphisms in the PPARGC1A gene on body fat in Asian Indians

To evaluate whether polymorphisms in the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) gene were related to body fat in Asian Indians. Three polymorphisms of PPARGC1A gene, the Thr394Thr, Gly482Ser and +A2962G, were genotyped on 82 type 2 diabetic and 82 normal glucose tolerant (NGT) subjects randomly chosen from the Chennai Urban Rural Epidemiology Study using PCR-RFLP, and the nature of the variants were confirmed using direct sequencing. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies using an expectation-maximization algorithm. Visceral, subcutaneous and total abdominal fat were measured using computed tomography, whereas dual X-ray absorptiometry was used to measure central abdominal and total body fat. None of the three polymorphisms studied were in LD. The genotype (0.59 vs 0.32, P=0.001) and allele (0.30 vs 0.17, P=0.007) frequencies of Thr394Thr polymorphism were significantly higher in type 2 diabetic subjects compared to those in NGT subjects. The odds ratio for diabetes (adjusted for age, sex and body mass index) for the susceptible genotype, XA (GA+AA) of Thr394Thr polymorphism, was 2.53 (95% confidence intervals: 1.30-5.04, P=0.009). Visceral and subcutaneous fat were significantly higher in NGT subjects with XA genotype of the Thr394Thr polymorphism compared to those with GG genotype (visceral fat: XA 148.2+/-46.9 vs GG 106.5+/-51.9 cm(2), P=0.001; subcutaneous fat: XA 271.8+/-167.1 vs GG 181.5+/-78.5 cm(2), P=0.001). Abdominal (XA 4521.9+/-1749.6 vs GG 3445.2+/-1443.4 g, P=0.004), central abdominal (XA 1689.0+/-524.0 vs GG 1228.5+/-438.7 g, P<0.0001) and non-abdominal fat (XA 18763.8+/-8789.4 vs GG 13160.4+/-4255.3 g, P<0.0001) were also significantly higher in the NGT subjects with XA genotype compared to those with GG genotype. The Gly482Ser and +A2962G polymorphisms were not associated with any of the body fat measures. Among Asian Indians, the Thr394Thr (G --> A) polymorphism is associated with increased total, visceral and subcutaneous body fat.