Dataset Information

Association of the PGC-1? rs8192678 variant with microalbuminuria in subjects with type 2 diabetes mellitus.

ABSTRACT: PPAR-? co-activator-1? (PGC-1?) is a tissue-specific transcriptional co-activator involved in the regulation of antioxidant enzymes. The A-allele of the rs8192678 PGC-1 ?} (G>A) gene variant has previously been associated with nephropathy in Korean and Indian-Asian type 2 diabetes mellitus (T2DM) samples. Our aim was to examine the association between this variant and urine albumin exccretion in European subjects with T2DM. Genotyping was performed on 583 European subjects with T2DM and examined in relation to urinary albumin, plasma oxidized-LDL and small dense-LDL percentage. We observed a significant association between genotype (GG/GA/AA) and urinary albumin (normoalbuminuria v micro/macroalbuminuria: 48.6/39.7/11.7% v 38.2/51.2/10.5%, p=0.02; for GG v GA/AA, p=0.01). The odds ratio for micro/macroalbuminuria in GA and AA subjects relative to GG were 1.70 [1.15-2.50], p=0.008 and 1.20 [0.66-2.16], p=0.56 respectively (for GA/AA v GG: 1.58 [95% CI: 1.09-2.27], p=0.02). There was a significant association between the A allele and a higher percentage of small dense-LDL particles (GG v GA v AA: 70.8 [58.01-81.06] % v 72.8 [56.18-81.19] % v 78.9 [67.16-85.33] %, p=0.03). In European subjects with T2DM the GA relative to the GG genotype is associated with a 70% increase in the risk of micro/microalbuminuria. Furthermore, homozygosity for the A-allele is also associated with a preponderance of small dense-LDL particles.

SUBMITTER: Prior SL

PROVIDER: S-EPMC3826894 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Association of the PGC-1α rs8192678 variant with microalbuminuria in subjects with type 2 diabetes mellitus.

Prior Sarah L SL Clark Amy R AR Jones Danielle A DA Bain Steve C SC Hurel Steve J SJ Humphries Steve E SE Stephens Jeffrey W JW

Disease markers 20120101 6

PPAR-γ co-activator-1α (PGC-1α) is a tissue-specific transcriptional co-activator involved in the regulation of antioxidant enzymes. The A-allele of the rs8192678 PGC-1 α} (G>A) gene variant has previously been associated with nephropathy in Korean and Indian-Asian type 2 diabetes mellitus (T2DM) samples. Our aim was to examine the association between this variant and urine albumin exccretion in European subjects with T2DM. Genotyping was performed on 583 European subjects with T2DM and examined ...[more]

PMID: 22684233

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Project description:BackgroundGenome-wide association study (GWAS) provides an unprecedented opportunity to reveal substantial genetic contribution to type 2 diabetes mellitus (T2DM) and glycemic identification of allelic heterogeneity and population-specific genetic variants, yet it also faces difficulty due to the vast amount of potential confounding factors and limited availability of clinical data. To identify responsible susceptibility loci and genomic polymorphism for T2DM and glycemic traits, we have systematically investigated a genome-wide association study related to T2DM. Although GWAS has captured many common genetic variations, which are related to T2DM, each risk allele (RA) of single-nucleotide polymorphisms (SNPs) at these loci is not conclusive. Therefore, it is common to present a combination of several SNPs to infer T2DM risk, yet it is still insufficient to be deterministic. To streamline the identification of a deterministic genetic variation in T2DM, we developed this meta-analysis as a showcase to comprehensively identify the association between cumulative RAs and T2DM risk by combining different studies in reported literature and databases. After all, we identified that PGC-1α rs8192678 polymorphism can be considered as a potentially deterministic biomarker in T2DM risk. Previous studies have potentially linked PGC-1α rs8192678 polymorphism to type 2 diabetes mellitus (T2DM) risk, but the results remain inconsistent in different populations and are not conclusive. We developed a new meta-analysis approach to systematically identify the association between PGC-1α rs8192678 polymorphism and T2DM, and we have comprehensively assessed different ethnic groups to validate our findings.MethodsWe performed comprehensive information retrieval and knowledge discovery meta-analysis by searching extensively published literature and different electronic databases to acquire eligible studies for the above association study. We developed a method to use pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) in five genetic models (allelic, dominant, recessive, homozygous, and heterozygous genetic models) to identify the relationship among ethnicity subgroup analyses comprehensively.ResultsWe identified 20 eligible studies consisting of 16,182 subjects (8,038 cases and 8,144 controls) in our meta-analysis. PGC-1α rs8192678 polymorphisms of all subjects showed a significant association with T2DM susceptibility under all genetic models: allelic (OR: 1.24, 95% CI: 1.13-1.35), dominant (OR: 1.27, 95% CI: 1.14-1.42), recessive (OR: 1.24, 95% CI: 1.14-1.36), homozygous (OR: 1.40, 95% CI: 1.20-1.64), and heterozygous (OR: 1.20, 95% CI: 1.06-1.35). In the subgroup analysis, we identified a significant association between PGC-1α rs8192678 polymorphism and T2DM in the Caucasian and Indian populations under all genetic models we investigated. This is the most comprehensive study of the subject to date.ConclusionOur development of meta-analysis revealed that the minor allele (A) carriers, especially AA genotype carriers, can lead to risk of T2DM in the Caucasian and Indian populations. This is the first report that such risk has been confirmed. Our finding shed new light into the genetic alteration in T2DM.

Project description:Aims/hypothesisPPARGC1A encodes peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), a central regulator of energy metabolism and mitochondrial function. A common polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been associated with obesity and related metabolic disorders, but no published functional studies have investigated direct allele-specific effects in adipocyte biology. We examined whether rs8192678 is a causal variant and reveal its biological function in human white adipose cells.MethodsWe used CRISPR-Cas9 genome editing to perform an allelic switch (C-to-T or T-to-C) at rs8192678 in an isogenic human pre-adipocyte white adipose tissue (hWAs) cell line. Allele-edited single-cell clones were expanded and screened to obtain homozygous T/T (Ser482Ser), C/C (Gly482Gly) and heterozygous C/T (Gly482Ser) isogenic cell populations, followed by functional studies of the allele-dependent effects on white adipocyte differentiation and mitochondrial function.ResultsAfter differentiation, the C/C adipocytes were visibly less BODIPY-positive than T/T and C/T adipocytes, and had significantly lower triacylglycerol content. The C allele presented a dose-dependent lowering effect on lipogenesis, as well as lower expression of genes critical for adipogenesis, lipid catabolism, lipogenesis and lipolysis. Moreover, C/C adipocytes had decreased oxygen consumption rate (OCR) at basal and maximal respiration, and lower ATP-linked OCR. We determined that these effects were a consequence of a C-allele-driven dysregulation of PGC-1α protein content, turnover rate and transcriptional coactivator activity.Conclusions/interpretationOur data show allele-specific causal effects of the rs8192678 variant on adipogenic differentiation. The C allele confers lower levels of PPARGC1A mRNA and PGC-1α protein, as well as disrupted dynamics of PGC-1α turnover and activity, with downstream effects on cellular differentiation and mitochondrial function. Our study provides the first experimentally deduced insights on the effects of rs8192678 on adipocyte phenotype.

Dataset Information

Association of the PGC-1? rs8192678 variant with microalbuminuria in subjects with type 2 diabetes mellitus.

Publications

Association of the PGC-1α rs8192678 variant with microalbuminuria in subjects with type 2 diabetes mellitus.

Similar Datasets

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