Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio

Genetics of Cardiovascular Disease: How Far Are We from Personalized CVD Risk Prediction and Management?

Despite the rapid progress in diagnosis and treatment of cardiovascular disease (CVD), this disease remains a major cause of mortality and morbidity. Recent progress over the last two decades in the field of molecular genetics, especially with new tools such as genome-wide association studies, has helped to identify new genes and their variants, which can be used for calculations of risk, prediction of treatment efficacy, or detection of subjects prone to drug side effects. Although the use of genetic risk scores further improves CVD prediction, the significance is not unambiguous, and some subjects at risk remain undetected. Further research directions should focus on the “second level” of genetic information, namely, regulatory molecules (miRNAs) and epigenetic changes, predominantly DNA methylation and gene-environment interactions

Telomere length as a predictor of emotional processing in the brain

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face‐related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing

Matrix degrading properties of sperm serine proteinase, acrosin

AbstractThe serine proteinase acrosin plays an important role in sperm penetration of the zona pellucida. In the present study we investigated the effect of the enzyme on various matrix proteins. Acrosin degraded proteolytically fibronectin, type IV collagen and heat denatured type I collagen, whereas neither native type I collagen nor laminin were cleaved by the enzyme. The specific activity of acrosin with type IV collagen as substrate (66.6 g/h/g) was 125-fold higher than that of known type IV collagenase or stromelysin. These results suggest that acrosin may act as a matrix-degrading proteinase

Cholesterol and the risk of acute coronary syndrome. Mendelian randomisation in the Czech population

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health, Czech Republic Introduction Increased plasma cholesterol levels are considered as a risk factor for the development of cardiovascular diseases, including acute coronary syndrome (ACS). However, observational studies in recent years have often found no increased LDL-cholesterol values in ACS patients compared to controls. Final cholesterol levels are largely modified by genetic factors, so they can be used to demonstrate (based on Mendelian randomization) whether the link between plasma cholesterol and MI risk is still present. Methods In our study, we analysed LDL-R (rs6511720), CILP2/PBX4 (rs16996148), APOB (rs693) and SORT-1 (rs646776) variants in a total of 939 patients with ACS and 1,191 healthy controls (post-MONICA study). Only men aged 18-65 years were included in the study. Results Patients with ACS had significantly lower total cholesterol levels than controls (4.8 ± 1.1 vs. 5.7 ± 1.1 mmol / L; P &amp;lt;0.001). Total and LDL-cholesterol were not higher in patients even after adjusting for age, BMI and dyslipidemic treatment. We confirmed a significant effect of all analysed variants on LDL-cholesterol levels (all P &amp;lt;0.01). None of the four analysed variants significantly affected the risk of MI (P values between 0.10 and 0.58). Individuals with at least seven cholesterol-raising alleles had a slightly increased risk of ACS compared to others (OR, 95% CI; 1.26, 1.06-1.51; P = 0.01). Conclusion Variants within the genes for LDL-R, CILP2 / PBX4, APOB and SORT-1 are significant genetic determinants of LDL-cholesterol levels in the population of Czech men. After a population-wide reduction in cholesterol levels, these levels no longer seem to be a serious problem in determining ACS, and interventions to reduce other types of risk should be given more attention. </jats:sec

Strong Gender-Specific Additive Effects of the NYD-SP18 and FTO Variants on BMI Values

The role of the FTO gene in obesity development is well established in populations around the world. The NYD-SP18 variant has been suggested to have a similar effect on BMI, but the role of this gene in determining BMI has not yet been verified. The objective of our study was to confirm the association between NYD-SP18 rs6971019 SNP and BMI in the Slavic population and to analyze i) the gender-specific effects of NYD-SP18 on BMI and ii) the simultaneous effect of FTO rs17817449 and NYD-SP18 on BMI. We analyzed a sample of a large adult population based on the post-MONICA study (1,191 males and 1,368 females). Individuals were analyzed three times over 9 years. NYD-SP18 rs6971019 SNP is related to BMI in males (2000/1 GG 28.3±3.7 kg/m2 vs. +A 27.5±3.7 kg/m2 P&lt;0.0005; in other examinations P&lt;0.05 and &lt;0.005), but not in females (all P values over 0.48 in all three examinations). Further analysis revealed the significant additive effect (but not the interaction) of FTO and NYD-SP18 SNPs on BMI in males (all P&lt;0.01). These results suggest that association between NYD-SP18 rs6971019 SNP and BMI may be restricted to males. Furthermore, variants within NYD-SP18 and FTO genes revealed a significant additive effect on BMI values in males.</jats:p