Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors

<p>Abstract</p> <p>Background</p> <p>High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR).</p> <p>Methods</p> <p>A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-α (< 1 μg/kg/week) and high-dose (≥1 μg/kg/week)).</p> <p>Results</p> <p>Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 μg/kg/week) vs usual-dose (0.5 μg/kg/week) ESA.</p> <p>In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (r_s= 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per μcg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05).</p> <p>Conclusion</p> <p>High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted.</p> <p>Trial registration</p> <p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00526747">NCT00526747</a></p

Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP