Alkaline phosphatase affects renal function in never-treated hypertensive patients. effect modification by age

Several studies in patients with chronic kidney disease or normal renal function have shown that high levels of tissue non-specific alkaline phosphatase (ALP) are associated with an increased risk of all cause and cardiovascular (CV) mortality. Considering the independent prognostic role of renal function, we investigated the possible association between ALP levels and estimated glomerular filtration rate (e-GFR) in a large cohort of hypertensive subjects. We enrolled 2157 never-treated uncomplicated hypertensive patients with ALP levels within normal range. In the whole population, e-GFR was strongly related to ALP (r = -0.43, P < 0.0001) with similar magnitude in females and in males, resulting ALP the second independent predictor of renal function. In a multiple linear regression model, both on crude (P < 0.001) and adjusted (P = 0.01) analyses age significantly modified the effect of a fixed increase in ALP (20 UI/L) on renal function so that the reduction in e-GFR associated to a 20 UI/L increase in ALP was of lower magnitude in younger patients and progressively of higher extent from 20 years of age onwards. In conclusion, present data indicate a significant relationship between ALP levels and e-GFR in uncomplicated hypertensive patients that is modulated by age and that persisted after adjusting for several confounders

Serum proprotein convertase subtilisin/Kexin type 9 and vascular disease in type 2 diabetic patients

BackgroundProprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels have been suggested as novel atherosclerotic biomarker. PCSK9 plays important roles in the pathogenesis of atherosclerosis by regulating the degradation of low-density lipoprotein receptor as well as different inflammatory pathways. Considering the important prognostic role of arterial stiffness in cardiovascular disease (CVD), the aim of the study is to investigate the correlation between PCSK9 levels and arterial stiffness in a cohort of diabetic patients, without previous CV events. MethodsThis cross-sectional analysis enrolled 401 Caucasian patients with type II diabetes mellitus (T2DM). PCSK9 levels were measured by ELISA test, arterial stiffness was estimated by measuring carotid-femoral pulse wave velocity (PWV). ResultsPatients were divided in three tertiles according to increasing value of PCSK9. From the I to the III tertiles, there was a significant increase in high sensitivity C-reactive protein (hs-CRP), fibrinogen and white blood cells (WBC) and a reduction in estimated glomerular filtration rate (e-GFR). Patients with higher levels of PCSK9 presented increased systolic, diastolic blood pressure, pulse pressure and PWV. PWV was significantly and directly correlated with PCSK9, fibrinogen, age, BMI and PP, and indirectly correlated with diet, lifestyle and e-GFR. Serum PCSK9 was the major predictor of PWV, justifying a 16.9% of its variation. ConclusionOur study demonstrates a close association between circulating PCSK9 levels and PWV in T2DM subjects without previous CV events even after adjusting for well-known CV risk factor and pharmacological medications. Serum PCSK9 could be a useful biomarker for CV risk stratification in diabetic subjects

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Different Patterns of Left Ventricular Hypertrophy in Metabolically Healthy and Insulin-Resistant Obese Subjects

Obese subjects showed different cardiovascular risk depending by different insulin sensitivity status. We investigated the difference in left ventricular mass and geometry between metabolically healthy (MHO) and unhealthy (MUHO) obese subjects. From a cohort of 876 obese subjects (48.3 ± 14.1 years) without cardio-metabolic disease and stratified according to increasing values of Matsuda index after 75 g oral glucose tolerance test, we defined MHO (n = 292) those in the upper tertile and MUHO (n = 292) those in the lower tertile. All participants underwent echocardiographic measurements. Left ventricular mass was calculated by Devereux equation and normalized by height2,7 and left ventricular hypertrophy (LVH) was defined by values >44 g/m2.7 for females and >48 g/m2.7 for males. Left ventricular geometric pattern was defined as concentric or eccentric if relative wall thickness was higher or lower than 0.42, respectively. MHO developed more commonly a concentric remodeling (19.9 vs. 9.9%; p = 0.001) and had a reduced risk for LVH (OR 0.46; p < 0.0001) than MUHO, in which the eccentric type was more prevalent (40.4 vs. 5.1%; p < 0.0001). We demonstrated that obese subjects-matched for age, gender and BMI-have different left ventricular mass and geometry due to different insulin sensitivity status, suggesting that diverse metabolic phenotypes lead to alternative myocardial adaptation

Osteopontin levels correlate with severity of diabetic cardiomyopathy in early stage of diabetes

Diabetic cardiomyopathy (DbCM) is characterized by restrictive pattern and consistent risk of overt heart failure. We here focused osteopontin (OPN), which was tested independently associated with left ventricular diastolic dysfunction (LVDD). Overall, OPN increased with DbCM severity according with the presence of left atrial dilatation, LV hypertrophy and LVDD

Osteopontin levels correlate with severity of diabetic cardiomyopathy in early stage of diabetes

Diabetic cardiomyopathy (DbCM) is characterized by restrictive pattern and consistent risk of overt heart failure. We here focused osteopontin (OPN), which was tested independently associated with left ventricular diastolic dysfunction (LVDD). Overall, OPN increased with DbCM severity according with the presence of left atrial dilatation, LV hypertrophy and LVDD