Abstract 050: Phenome Wide Association Study of IL6R Variants Identifies a Drug Target for Cardiovascular Disease and Inflammation

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Tianxi Cai ◽  
Yichi Zhang ◽  
Yuk-Lam Ho ◽  
Nicholas Link ◽  
Jie Huang ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Association Study ◽  
Regression Models ◽  
Strong Association ◽  
Drug Effects ◽  
Aortic Aneurysms ◽  
Unexpected Result ◽  
Routine Laboratory ◽  
Linear Regression Models ◽  
Laboratory Measurements

Background: Individuals with an interleukin 6 receptor (IL6R) genetic variant not on IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. Thus, studying whether the IL6R variant is protective for a phenotype can inform which diseases may benefit from treatment with IL6R blockade. To test this hypothesis, we performed a Phenome-Wide Association Study (PheWAS) to screen for associations between an IL6R variant and a broad range of phenotypes in the electronic health records (EHR). Methods: We studied veteran participants in the Veteran’s Affairs Million Veteran’s Project using genomic data linked to EHR. We extracted all diagnoses codes and mapped them to phenotype groups using published PheWAS methods. Routine laboratory measurements, e.g. liver function tests, were also extracted. A PheWAS was performed by constructing logistic regression models testing associations between the IL6R variant (Asp358Ala, rs2228145) and 1,866 phenotype groups; linear regression models were constructed to screen for associations between IL6R and 26 routine laboratory measurements. All models were adjusted for age, gender, and race. Significance was reported using false discovery rate ≤0.05 and Bonferroni correction. Results: We studied 342,529 participants; the minor allele frequency of the IL6R variant was 35.3%. IL6R was most strongly associated with a reduced risk of aortic aneurysm (OR 0.91-0.92, 95% CI 0.89, 0.94) (Figure 1). We observed the expected association between IL6R and reduced C-reactive protein. We also observed known side effects of IL6R blockade, elevated transaminases, as well as elevated triglycerides, an initially unexpected result in the early clinical trials. Conclusion: In this proof of concept study, we demonstrate the utility of PheWAS to inform drug effects using the largest US-based biobank study. The strong association with aortic aneurysm corresponded with the newest indication for IL6R blockade to prevent aortic aneurysms due to large vessel vasculitis.

Factors Associated With Completion: Pathways Through Developmental Mathematics

2020 ◽  
pp. 152102511990098
Author(s):  
Elizabeth Howell ◽  
Candace Walkington
Keyword(s):  
Community College ◽  
Developmental Mathematics ◽  
Regression Models ◽  
Strong Association ◽  
Full Time ◽  
Linear Regression Models ◽  
Logistic Regression Models ◽  
Factors Associated ◽  
Mathematics Coursework ◽  
Time Required

This study examines two 5-year longitudinal data sets of community college students ( n = 595 and n = 593) to explore factors associated with successful outcomes in developmental mathematics. Logistic regression models consider the role of demographic factors, course format, and student support structures on the likelihood of a student completing the developmental sequence and subsequently passing a credit-level mathematics course. Additional linear regression models examine the time required to complete developmental coursework. Tutoring has a strong association with positive student outcomes, as does full-time enrollment and developmental mathematics coursework grades. Alternative course formats are also associated with increased likelihood of success for students, but some alternative formats delay a student's time line. Implications for developmental mathematics programs in community college settings are discussed.

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Diehm ◽  
Schmidli ◽  
Dai-Do ◽  
Baumgartner
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Medical Treatment ◽  
Endovascular Treatment ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Current Evidence ◽  
Significant Morbidity ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome

VASA ◽  
2017 ◽  
Vol 46 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Alejandra María Zúñiga-Muñoz ◽  
Israel Pérez-Torres ◽  
Verónica Guarner-Lans ◽  
Elías Núñez-Garrido ◽  
Rodrigo Velázquez Espejel ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Aortic Aneurysms ◽  
Aortic Dilatation ◽  
Glutathione S Transferase ◽  
Reduced And Oxidized Glutathione ◽  
Total Antioxidant ◽  
Elevated Activity ◽  
Acute Dissection ◽  
Thoracic Aneurysms

Abstract. Background: Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. Patients and methods: Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. Results: LPO index, carbonylation, TGF-β1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). Conclusions: The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

Gender differences in abdominal aortic aneurysm therapy – a systematic review

VASA ◽  
2018 ◽  
Vol 47 (4) ◽  
pp. 267-272 ◽  
Author(s):  
Konstanze Stoberock ◽  
Tilo Kölbel ◽  
Gülsen Atlihan ◽  
Eike Sebastian Debus ◽  
Nikolaos Tsilimparis ◽  
...  
Keyword(s):  
Gender Differences ◽  
Abdominal Aortic Aneurysm ◽  
Survival Rate ◽  
Aortic Aneurysm ◽  
Endovascular Treatment ◽  
Aortic Aneurysms ◽  
Lower Survival Rate ◽  
Lower Survival ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abstract. This article analyses if and to what extent gender differences exist in abdominal aortic aneurysm (AAA) therapy. For this purpose Medline (PubMed) was searched from January 1999 to January 2018. Keywords were: “abdominal aortic aneurysm”, “gender”, “prevalence”, “EVAR”, and “open surgery of abdominal aortic aneurysm”. Regardless of open or endovascular treatment of abdominal aortic aneurysms, women have a higher rate of complications and longer hospitalizations compared to men. The majority of studies showed that women have a lower survival rate for surgical and endovascular treatment of abdominal aneurysms after both elective and emergency interventions. Women receive less surgical/interventional and protective medical treatment. Women seem to have a higher risk of rupture, a lower survival rate in AAA, and a higher rate of complications, regardless of endovascular or open treatment. The gender differences may be due to a higher age of women at diagnosis and therapy associated with higher comorbidity, but also because of genetic, hormonal, anatomical, biological, and socio-cultural differences. Strategies for treatment in female patients must be further defined to optimize outcome.

Epigenetic Profiling Identifies Novel Genes for Ascending Aortic Aneurysm Formation with Bicuspid Aortic Valves

2015 ◽  
Vol 18 (4) ◽  
pp. 134 ◽  
Author(s):  
Asad A Shah
Keyword(s):  
Gene Expression ◽  
Aortic Aneurysm ◽  
Methylation Status ◽  
Aortic Aneurysms ◽  
Aortic Valves ◽  
Ascending Aortic Aneurysm ◽  
Novel Genes ◽  
Aneurysm Formation ◽  
Aortic Replacement ◽  
Bicuspid Aortic Valves

<p><strong>Background:  </strong>Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized.  We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.</p><p><strong>Methods:  </strong>Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves.  Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays.  Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test.  </p><p><strong>Results:  </strong>Twenty-seven probes in 9 genes showed significant differential methylation and expression (P&lt;5.5x10<sup>-4</sup>).  The top gene was protein tyrosine phosphatase, non-receptor type 22 (<em>PTPN22</em>), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10<sup>-5</sup>) in bicuspid patients, as compared to tricuspid patients.  Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including <em>ACTA2</em> (4 probes, delta beta range:  -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissections</p><p><strong>Conclusions:  </strong>Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms.  The top gene was <em>PTPN22</em>, which is involved in T-cell receptor signaling and associated with various immune disorders.  These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.</p>

FAKTOR DETERMINAN PENYALURAN KREDIT BANK PERSERO

2018 ◽  
Vol 23 (1) ◽  
pp. 60-71
Author(s):  
Wigiyanti Masodah
Keyword(s):  
Interest Rate ◽  
Linear Regression ◽  
Interest Rates ◽  
Regression Models ◽  
Linear Regression Models ◽  
Negative Impacts ◽  
Main Activity ◽  
The Impact ◽  
The Given ◽  
Multiple Linear Regression Models

Offering credit is the main activity of a Bank. There are some considerations when a bank offers credit, that includes Interest Rates, Inflation, and NPL. This study aims to find out the impact of Variable Interest Rates, Inflation variables and NPL variables on credit disbursed. The object in this study is state-owned banks. The method of analysis in this study uses multiple linear regression models. The results of the study have shown that Interest Rates and NPL gave some negative impacts on the given credit. Meanwhile, Inflation variable does not have a significant effect on credit given. Keywords: Interest Rate, Inflation, NPL, offered Credit.

Linear Regression Models for Interval-Valued Data using Log-transformation

2020 ◽  
Author(s):  
Nykolas Mayko Maia Barbosa ◽  
João Paulo Pordeus Gomes ◽  
César Lincoln Cavalcante Mattos ◽  
Diêgo Farias Oliveira
Keyword(s):  
Linear Regression ◽  
Regression Models ◽  
Linear Regression Models ◽  
Log Transformation ◽  
Interval Valued

THE PREDICTIVE CONTENT OF DISAGGREGATED NORMAL INCOME: An Empirical Study in the JSX

2003 ◽  
Vol 5 (3) ◽  
pp. 363 ◽  
Author(s):  
Slamet Sugiri
Keyword(s):  
Linear Regression ◽  
Regression Models ◽  
Stock Exchange ◽  
Manufacturing Firms ◽  
Single Step ◽  
Model Parameters ◽  
Linear Regression Models ◽  
Operating Income ◽  
Predictive Content ◽  
Multiple Step

The main objective of this study is to examine a hypothesis that the predictive content of normal income disaggregated into operating income and nonoperating income outperforms that of aggregated normal income in predicting future cash flow. To test the hypothesis, linear regression models are developed. The model parameters are estimated based on fifty-five manufacturing firms listed in the Jakarta Stock Exchange (JSX) up to the end of 1997.This study finds that empirical evidence supports the hypothesis. This evidence supports arguments that, in reporting income from continuing operations, multiple-step approach is preferred to single-step one.

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