Inappropriate statin therapy according to ASCVD risk: Can we do better?

Background: Statin therapy targeted at reducing 10-year risk of ASCVD has become a cornerstone of preventative health in the outpatient setting. Appropriate statin prescription can lead to improved morbidity and mortality as outlined by current American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Methods: In this empiric observational study performed in August 2018, we calculated the 10-year ASCVD risk for patients visiting the Henry Ford Hospital Academic Internal Medicine Clinic between January and December 2017, and compared the ACC/AHA guideline recommended statin intensity with the one currently prescribed. Our aim was to assess appropriateness of statin therapy based on ASCVD risk calculation and ACC/AHA guidelines. Results: Of the 2994 patients assessed, approximately 1548 patients were prescribed an inappropriate intensity of statin based on 10-year ASCVD risk calculation (p \u3c 0.001). For female patients, the odds of appropriate statin dose prescription increased by approximately 81.9% (odds ratio 1-1.819) when compared to male patients (95% CI 1.559-2.124). For black patients, the odds of appropriate statin prescription decreased by 32.2% (odds ratio 1-0.678) when compared to white patients (95% CI 0.532-0.864). Approximately 1245 patients currently taking high-intensity statin did not qualify for one as compared to 484 patients (p \u3c 0.001). Conclusion: Calculation of 10-year ASCVD risk is an integral part of guiding statin prescription and preventative health therapy in the outpatient setting, However, an increasing percentage of patients are not managed adequately according to ACC/AHA guidelines. Race, gender, and income disparities appear to be major factors influencing appropriateness of statin prescription. This demonstrates a major opportunity for potential intervention to improve statin prescription and patient health outcomes.https://scholarlycommons.henryford.com/merf2019hcd/1000/thumbnail.jp

Human miRNAs: an antiviral defense mechanism

Background miRNAs are short 21-24 nt RNAs that mediate post transcriptional repression of target genes. Various reports have shown that miRNAs are capable of repressing the gene expression levels of different viruses, leading to the suggestion that miRNAs are key mediators of host-virus interaction [1]. HIV-1 is a retrovirus known to cause AIDS, one of the major diseases in humans. The nef gene of the HIV-1 has been shown to be important for virus repression of CD4+ cells and virus progression. It has also been shown earlier that patients infected with nef deleted HIV-1 do not progress from infected to diseased state for longer periods of time, resulting in the Long Term Non-Progressor phenotype [2]. Materials and methods We computationally predicted five endogenously expressed human miRNAs to target the nef gene of HIV-1 retrovirus. On applying other stringency parameters we could focus on two of the five miRNAs viz. hsa-mir-29a and hsa-mir-29b as they were predicted to target the nef gene, at sites highly conserved amongst other clades of HIV-1 [3]. We then created reporter carrying the nef gene inserted downstream of a luciferase reporter. miRNA expression vectors were also made which would express the pri-miRNA when processed and thereby lead to high levels of the miRNA inside the cells. We then identified various cell lines for validating nef as a target for hsa-mir-29a and hsa-mir-29b. Results and discussion Gene reporter assays and ectopic over-expression of miRNAs conclusively showed that human cellular miRNAs hsa-mir-29a and hsa-mir-29b could bring down the nef protein levels and also affect viral replication [4]. These results would provide a better understanding of the mechanisms that could regulate the viral gene expression and human cellular antiviral defense mechanisms whereby miRNAs could serve as potential therapeutics to treat various viral diseases

Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication

protein expression and HIV-1 replicatio

Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study

Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P 1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Inappropriate Statin Therapy According to Atherosclerotic Cardiovascular Disease (ASCVD) Risk: Can We Do Better?

Background: Statin therapy targeted at reducing 10-year risk of stroke and heart attack has become a cornerstone for preventative health in the outpatient setting. Appropriate statin intensity prescription based on 10-year ASCVD risk calculation can lead to improved morbidity and mortality as outlined by current American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Methods: We conducted an empiric observational study in August 2018 based on lab Results of patients visiting the Henry Ford Hospital Academic Internal Medicine Clinic between January 2017 and December 2017. We calculated the 10-year ASCVD risk for the patients based on this data, and compared the ACC/AHA guideline recommended statin therapy with the one currently prescribed. The primary outcome was appropriateness of statin therapy based on ASVCD risk calculation. Our aim was to assess whether patients in the clinic setting are being adequately managed for ASCVD risk according to ACC/AHA guidelines. Results: Of the 2994 patients assessed, approximately 1548 patients were prescribed an inappropriate intensity of statin based on 10-year ASCVD risk calculation (p \u3c 0.001). For female patients, the odds of appropriate statin dose prescription increased by approximately 81.9% (odds ratio 1-1.819) when compared to male patients (95% CI 1.559-2.124). For black patients, the odds of appropriate statin dose prescription decreased by 32.2% (odds ratio 1-0.678) when compared to white patients (95% CI 0.532-0.864). Asian patients were more likely to be on an appropriate statin dose as compared to non-Asians (p = 0.022), and Hispanic patients were more likely to be on an appropriate statin dose as compared to non-Hispanics (p = 0.005). Approximately 1245 patients currently taking high-intensity statin did not qualify for one based on 10-year ASCVD risk calculation as compared to 484 patients (p \u3c 0.001). Conclusions: There is marked discrepancy in the guideline recommended statin therapy (based on 10-year ASCVD risk calculation) and currently prescribed statin, with gender and race serving as major variables. This data demonstrates a major opportunity for intervention on the part of primary care internists to improve patient outcomes in the outpatient setting

A hexanucleotide repeat upstream of eotaxin gene promoter is associated with asthma, serum total IgE and plasma eotaxin levels

Background: Eotaxin (CCL11) is a small protein produced in the lungs of patients with asthma, and is a potent chemoattractant for eosinophils. Aim: To elucidate the role of eotaxin in asthma by an association study of functional and novel eotaxin polymorphisms in case-control and family-based study designs. Methods:Eotaxin +67G/A, -384A/G and -426C/T single-nucleotide polymorphisms and a hexanucleotide (GAAGGA)n repeat 10.9 kb upstream of the gene were genotyped in a cohort of age, sex and ethnically matched patients with asthma (n = 235) and healthy controls (n = 239), and also in a study population of 230 families with asthma recruited from north/northwest India. Total serum IgE (TsIgE) and plasma eotaxin levels were measured using ELISA. Results: +67G/A polymorphism was found to be significantly associated with asthma in case-control (p = 0.009) and family-based studies (p = 0.006). Its functional role, as it was correlated with plasma eotaxin levels (p = 0.006), was also demonstrated. Further, -384C/T single-nucleotide polymorphism was found to be significantly associated with log10 TsIgE (p = 0.016 in case-control and p = 0.018 in families) and eotaxin levels (p = 0.007). Most interestingly, for the first time, a highly significant association of the newly studied (GAAGGA)n hexanucleotide repeat with asthma (p = 3×10-6), log10TsIgE (p = 0.006) and eotaxin levels (p = 0.004) was observed. G_A_C_8 was also identified as an important risk haplotype associated with high TsIgE and plasma eotaxin levels. Conclusions: This study provides further evidence that eotaxin polymorphisms are associated with the development of asthma by regulating eotaxin levels and reinforces towards the scanning of other chemokine genes present at 17q21 locus for their association with asthma and related phenotypes

Identification and Validation of a Putative Polycomb Responsive Element in the Human Genome

<div><p>Epigenetic cellular memory mechanisms that involve polycomb and trithorax group of proteins are well conserved across metazoans. The <i>cis</i>-acting elements interacting with these proteins, however, are poorly understood in mammals. In a directed search we identified a potential polycomb responsive element with 25 repeats of YY1 binding motifthatwe designate PRE-PIK3C2B as it occurs in the first intron of human <i>PIK3C2B</i> gene. It down regulates reporter gene expression in HEK cells and the repression is dependent on polycomb group of proteins (PcG). We demonstrate that PRE-PIK3C2B interacts directly with YY1 <i>in vitro</i> and recruits PRC2 complex <i>in vivo</i>. The localization of PcG proteins including YY1 to PRE-PIK3C2B in HEK cells is decreased on knock-down of either <i>YY1</i> or <i>SUZ12</i>. Endogenous PRE-PIK3C2B shows bivalent marking having H3K27me3 and H3K4me3 for repressed and active state respectively. In transgenic <i>Drosophila</i>, PRE-PIK3C2B down regulates mini-white expression, exhibits variegation and pairing sensitive silencing (PSS), which has not been previously demonstrated for mammalian PRE. Taken together, our results strongly suggest that PRE-PIK3C2B functions as a site of interaction for polycomb proteins.</p></div