mRNA PGC-1α levels in blood samples reliably correlates with its myocardial expression: study in patients undergoing cardiac surgery

et al.[Objective]: Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that has been proposed to play a protective role in mouse models of cardiac ischemia and heart failure, suggesting that PGC-1α could be relevant as a prognostic marker. Our previous studies showed that the estimation of peripheral mRNA PGC-1α expression was feasible and that its induction correlated with the extent of myocardial necrosis and left ventricular remodeling in patients with myocardial infarction. In this study, we sought to determine if the myocardial and peripheral expressions of PGC-1α are well correlated and to analyze the variability of PGC-1α expression depending on the prevalence of some metabolic disorders. [Methods]: This was a cohort of 35 consecutive stable heart failure patients with severe aortic stenosis who underwent an elective aortic valve replacement surgery. mRNA PGC-1α expression was simultaneously determined from myocardial biopsy specimens and blood samples obtained during surgery by quantitative PCR, and a correlation between samples was made using the Kappa index. Patients were divided into two groups according to the detection of baseline expression levels of PGC-1α in blood samples, and comparisons between both groups were made by chi-square test or unpaired Student’s t-test as appropriate. [Results]: Based on myocardial biopsies, we found that mRNA PGC-1α expression in blood samples showed a statistically significant correlation with myocardial expression (Kappa index 0.66, p<0.001). The presence of higher systemic PGC-1α expression was associated with a greater expression of some target genes such as silent information regulator 2 homolog-1 (x-fold expression in blood samples: 4.43±5.22 vs. 1.09±0.14, p=0.044) and better antioxidant status in these patients (concentration of Trolox: 0.40±0.05 vs. 0.34±0.65, p=0.006). [Conclusions]: Most patients with higher peripheral expression also had increased myocardial expression, so we conclude that the non-invasive estimation of mRNA PGC-1α expression from blood samples provides a good approach of the constitutive status of the mitochondrial protection system regulated by PGC-1α and that this could be used as prognostic indicator in cardiovascular disease.Grant from Sociedad Valenciana de Cardiología, 2013 to Óscar Fabregat-Andrés.Peer Reviewe

Genetic Variation in <i>PSCA</i> and Risk of Gastric Advanced Preneoplastic Lesions and Cancer in Relation to <i>Helicobacter pylori</i> Infection

<div><p>SNPs in the Prostate Stem Cell Antigen (<i>PSCA</i>) gene have been found associated with gastric cancer (GC) risk in a genome-wide association study. This association has been replicated in several populations. In this study we assessed the impact of <i>PSCA</i> genotype on the risk of advanced gastric precancerous lesions and GC. We used baseline gastric histopathology data and DNA from frozen gastric biopsies of 2045 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela, and 180 cases of GC from the same area. We analyzed 3 SNPs in the <i>PSCA</i> gene (rs2294008, rs9297976 and rs12155758) which were previously found to be associated with GC risk in Europeans. The T allele of rs2294008 was found to be associated with a higher prevalence of atrophic gastritis (OR = 1.44; 95% CI 1.03–2.01 for the dominant model) and intestinal metaplasia (OR = 1.50; 95% CI 1.13–1.98 for the dominant model). We also confirmed the association with higher risk of gastric cancer (OR = 2.34; 95% CI 1.36–4.01 for the allele carriers). SNP rs12155758 was not associated with risk of gastric preneoplastic lesions, but we confirmed its association with higher GC risk (OR 1.95; 95% CI 1.29–2.97 for dominant model). We tested the relevance of the presence of the <i>Helicobacter pylori cagA</i> gene, which is known to increase the risk of more severe gastric lesions, but we did not find any clearcut interaction with <i>PSCA</i> SNPs in defining risk of gastric precancerous lesions or cancer.</p></div

ORs for gastric cancer cases stratified by histology and anatomic localization, in comparison with normal or non-atrophic gastritis, according to individual <i>PSCA</i> SNPs.

<p>Odds ratios were adjusted for age, gender, smoking status, length of refrigerator use, educational level. Values in bold are statistically significant (p<0.004), in italic p-value<0.017 (p = 0.05/3 polymorphisms).</p

ORs for precancerous lesions and GC, in comparison with normal or non-atrophic gastritis, according to individual <i>PSCA</i> SNPs.

<p>Odds ratios were adjusted for age, gender, smoking status, length of refrigerator use, educational level. Values in bold are statistically significant (p<0.004), in italic p-value<0.017 (p = 0.05/3 polymorphisms).</p

ORs for pre-neoplastic lesions and gastric cancer cases stratified by diagnosis and <i>cagA</i> status, in comparison with normal or non-atrophic gastritis, according to individual <i>PSCA</i> SNPs.

<p>Odds ratios were adjusted for age, gender, smoking status, length of refrigerator use, educational level. <i>cagA</i> negative includes subjects who were not infected by <i>H. pylori</i> (187 subjects)and subjects who were infected by <i>H. pylori</i> but carried a <i>cagA</i>-negative strain (604 subjects). Values in bold are statistically significant (p<0.004), in italic p-value<0.017 (p = 0.05/3 polymorphisms).</p

Scheme of the alignment of the EPIYA motifs with number of observations in Mexican and Venezuelan populations.

<p>Scheme of the alignment of the EPIYA motifs with number of observations in Mexican and Venezuelan populations.</p

Characteristics of the populations and numbers of Mexican and Venezuelan samples for individual genes and regions of <i>cagA</i> analyzed.

<p>Characteristics of the populations and numbers of Mexican and Venezuelan samples for individual genes and regions of <i>cagA</i> analyzed.</p

Summary of thirty-one SNPs (10 non-synonymous and 21 synonymous) showing statistically significant differences (P<0.05) between gastritis and gastric cancer cases.

<p>The color coding is as follows: SNPs in green are synonymous variants, SNPs in blue are not synonymous variants and SNPs in red are those with strong statistical significance (study-wise threshold of P = 1.31×10⁻⁴).</p

Synonymous variants with a frequency greater than 20% in all samples and more of 25% difference in the prevalence between cancer and gastritis or the prevalence in one group at least twice as high as in the other group.

a<p>Reference strain 26695 (reference in GenBank: NC_000915).</p>b<p>OR =  odds ratio; CI = confidence interval</p

Bar chart of age by genotypes showing the association between the polymorphism of <i>TAS2R16</i> rs 978739 and longevity.

<p>The A/A genotype frequency is about 40.5% in the young and adult classes (20–50 and 51–70 years). Thereafter the A/A frequency increases through older classes reaching the 55.5% in the oldest (χ² = 17,08, p<0.029).</p