scholarly journals Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke

2021 ◽  
Author(s):  
Jaakko Leskelä ◽  
Iiro Toppila ◽  
Mari‐Anne Härma ◽  
Teemu Palviainen ◽  
Aino Salminen ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Lipoprotein Metabolism ◽  
Coagulation Cascade ◽  
Genetic Profile ◽  
Contact Activation ◽  
Genome Wide ◽  
A Genome ◽  
Cardiometabolic Disorders

Background Translocation of lipopolysaccharide from gram‐negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome‐wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high‐performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis‐related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome‐wide significant association with 741 single‐nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1 , KLKB1 , F12 , SLC34A1 , YPEL4 , CLP1 , ZDHHC5 , SERPING1 , CBX5 , and LIPC . The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.

scholarly journals A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging

2019 ◽  
Author(s):  
Janice L Atkins ◽  
Juulia Jylhävä ◽  
Nancy L Pedersen ◽  
Patrik K Magnusson ◽  
Yi Lu ◽  
...  
Keyword(s):  
Association Study ◽  
Risk Score ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Genetic Risk Score ◽  
Frailty Index ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome

ABSTRACTFrailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. The mechanisms underlying frailty are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 19 and 45%. Understanding the genetic determinants and biological mechanisms underpinning frailty may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) of a frailty index (FI) in European descent participants from UK Biobank (n=164,610, aged 60-70 years). FI calculation was based on 49 self-reported items on symptoms, disabilities and diagnosed diseases. We identified 26 independent genetic signals at 24 loci associated with the FI (p<5*10−8). Many of these loci have previously been associated with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, three appear to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 14% (0.14, SE 0.006). A genetic risk score for the FI, derived solely from the UK Biobank data, was significantly associated with FI in the Swedish TwinGene study (n=10,616, beta: 0.11, 95% CI: 0.02-0.20, p=0.015). In pathway analysis, genes associated with synapse function were significantly enriched (p<3*10−6). We also used Mendelian randomization to identify modifiable traits and exposures that may affect the risk of frailty, with a higher educational attainment genetic risk score being associated with a lower risk of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on synapse maintenance pathways.

scholarly journals Predictors of Relapse in a Bupropion Trial for Smoking Cessation in Recently-Abstinent Alcoholics: Preliminary Results Using an Aggregate Genetic Risk Score

2012 ◽  
Vol 6 ◽  
pp. SART.S8866 ◽  
Author(s):  
John E. McGeary ◽  
Valerie S. Knopik ◽  
John E. Hayes ◽  
Rohan H. Palmer ◽  
Peter M. Monti ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Response To Treatment ◽  
Genetic Profile ◽  
Smoking Cessation Treatment ◽  
Cessation Treatment ◽  
The Us ◽  
Medication Intervention

Introduction Rates of smoking in the US population have decreased overall, but rates in some groups, including alcoholic smokers, remain high. Many newly sober alcoholics are concerned about their smoking and some attempt to quit. However, quit rates in this population are low. Prior studies suggest risk for relapse in this population may be genetically influenced and that genetic factors may moderate response to treatment. Methods In this exploratory study, we had two specific aims: (1) to investigate associations between genetic risk and outcome; (2) to investigate whether genetic risk moderates the efficacy of a medication intervention. Data are from a subsample of 90 participants from a clinical trial of smoking cessation treatment for smokers with between 2 and 12 months of alcohol abstinence. Subjects were randomly assigned to bupropion or placebo. All subjects received counseling and nicotine patches. To examine the possibility that bupropion may have been efficacious in participants with a specific genetic profile (ie, a pharmacogenetic approach), an aggregate genetic risk score was created by combining risk genotypes previously identified in bupropion treatment studies. Results Although medication efficacy was not moderated by the aggregate genetic risk score, there was an interaction between nicotine dependence and genetic risk in predicting smoking abstinence rates at the end of treatment (10 weeks). Conclusions Results suggest an aggregate genetic risk score approach may have utility in treatment trials of alcoholics who smoke. Additionally, these findings suggest a strategy for understanding and interpreting conflicting results for single genetic markers examined as moderators of smoking cessation treatment.

scholarly journals Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins

2020 ◽  
Author(s):  
Waheed-Ul-Rahman Ahmed ◽  
Akira Wiberg ◽  
Michael Ng ◽  
Wei Wang ◽  
Adam Auton ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Varicose Veins ◽  
Genetic Risk Score ◽  
Therapeutic Targets ◽  
Genome Wide Association ◽  
Western Society ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
Novel Therapeutic

AbstractBackgroundVaricose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.MethodsWe performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.ResultsWe discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.ConclusionsGenes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.

Abstract 175: Performance of a Multilocus Genetic Risk Score Derived from Top Signals in the Cardiogram+C4d Consortium in Predicting Incident Coronary Disease in the Atherosclerosis Risk in Communities Study

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Themistocles L Assimes ◽  
Benjamin Goldstein ◽  
Keyword(s):  
Risk Prediction ◽  
Risk Score ◽  
Genetic Risk ◽  
Association Studies ◽  
Genetic Risk Score ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genotype Information ◽  
Atherosclerosis Risk

Genome wide association studies (GWAS) to date have identified 30 CAD susceptibility loci but the ability to use this information to improve risk prediction remains limited. A meta-analysis of the GWAS and Cardio Metabochip data produced by the CARDIoGRAM+C4D consortium representing 63,253 cases and 126,820 controls has identified 1885 SNPs passing a False Discovery Rate (FDR) threshold of 0.5%. We hypothesized that an expanded multi locus genetic risk score (GRS) incorporating genotype information at all loci below an FDR of 0.5% would perform better than a GRS restricted to 42 loci reaching genome wide significance and tested this hypothesis in subjects of European ancestry participating in the Atherosclerosis Risk in the Community (ARIC) study. Models testing the GRS were either minimally (age and sex) or fully adjusted for traditional risk factors (TRFs). The Figure shows the hazard ratio (HZ) and 95% CI for incident events comparing each quintile of GRS to the middle quintile. The GRS including genotype information at all loci with an FDR of 0.5% noticeably improves risk prediction over the GRS restricted to genome wide significant loci in both the minimally and fully adjusted models based on several metrics including i) HR per GRS quintile, ii) the HR per SD of the GRS, and iii) the logistic regression pseudo R2, and iv) the c statistic. The HR per GRS quintile and per SD of GRS were all lower in the fully adjusted models compared to the respective minimally adjusted models but the reduction of the HR was more striking for the models that tested the more expansive GRS. These findings suggest that a larger proportion of novel GWAS CAD loci are mediating their effects through TRFs. While these findings demonstrate some progress in risk prediction using GWAS loci, both the limited and the expanded GRS continues to explain a relatively small proportion of the overall variance compared to TRF. Thus, the clinical utility of a CAD GRS remains to be determined.

scholarly journals Polygenic risk for coronary artery disease in the Scottish and English population

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chuhua Yang ◽  
Fabian Starnecker ◽  
Shichao Pang ◽  
Zhifen Chen ◽  
Ulrich Güldener ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Individual Risk ◽  
Risk Alleles ◽  
Genome Wide ◽  
Artery Disease ◽  
Cad Risk

Abstract Background Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods Using UK Biobank (UKB) data, we assessed CAD risk, based on the Framingham risk score (FRS) and common genetic variants, to explore the respective contribution to CAD prevalence in Scotland (n = 31,963) and England (n = 317,889). We calculated FRS based on sex, age, body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk. Results Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P < 0.001). However, the FRS only predicted a marginally higher CAD risk (less than 1%) in Scotland (12.5 ± 10.5 vs.12.6 ± 10.6, P = 0.03). Likewise, the overall number of genome-wide significant variants affecting CAD risk (157.6 ± 7.7 and 157.5 ± 7.7; P = 0.12) and a wGRS for CAD (2.49 ± 0.25 in both populations, P = 0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences in the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here, 35 variants had higher frequencies in Scotland, whereas 37 had higher frequencies in England (P < 0.001 each). Conclusions Neither the traditional risk factors included in the FRS nor a genetic risk score (GRS) based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles, which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

scholarly journals Genome Wide Pleiotropic Analysis to Identify Novel Variants and Improve Genetic Risk Score Construction

2021 ◽  
Author(s):  
Xiaofeng Zhu ◽  
Luke Zhu ◽  
Heming Wang ◽  
Richard Cooper ◽  
Aravinda Chakravarti
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Modifiable Risk Factors ◽  
Summary Statistics ◽  
Genome Wide ◽  
Novel Variants ◽  
Highly Correlated ◽  
Insight Into

Abstract Systolic and diastolic blood pressure (S/DBP) are highly correlated and modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and GWAS pleiotropy analysis of S/DBP summary statistics from large published BP GWAS and construct a composite genetic risk score (GRS), capturing respectively 21%, 11%, and 227% more of SBP, DBP and PP heritability than achieved with the traditional GRS. The composite GRS improves the prediction of hypertension and CVD in persons of European as well as African and Asian descent. We identified and confirmed 120 novel BP pleiotropic variants that are not in linkage disequilibrium with known variants, including 17 novel BP loci. We further observed significant age-modulated genetic effects on BP, hypertension and CVD in both Europeans and Asians. Our study provides further insight into BP regulation and provides a novel way to construct a GRS for correlated traits.

Will patient’s genetic profile help to choose treatment method of atrial fibrillation?

2019 ◽  
Vol 3 (52) ◽  
pp. 29-30
Author(s):  
Artur Fuglewicz
Keyword(s):  
Atrial Fibrillation ◽  
Single Nucleotide Polymorphisms ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Treatment Method ◽  
Genetic Profile ◽  
Nucleotide Polymorphisms ◽  
Genetic Score ◽  
Single Nucleotide

The paper comments an attempt of genetic score creation of potential atrial fibrillation ablation failure or recurrence AF. This genetic risk score is based on single nucleotide polymorphisms (SNPs) analysis.

scholarly journals Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism

2016 ◽  
Vol 116 (10) ◽  
pp. 705-713 ◽  
Author(s):  
Marta Crous-Bou ◽  
Immaculata De Vivo ◽  
Carlos A. Camargo ◽  
Raphaëlle Varraso ◽  
Francine Grodstein ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Risk Score ◽  
Environmental Risk ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Environmental Risk Factors ◽  
Health Study ◽  
Targeted Prevention ◽  
Genome Wide

SummaryMultiple genetic and environmental risk factors contribute to venous thromboembolism (VTE) risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of VTE and may identify opportunities for targeted prevention and treatment. It was our aim to examine the main effects and the potential effect-modification between single nucleotide polymorphisms (SNPs) at established loci and lifestyle risk factors for VTE. We performed a nested case-control study using data on 1,040 incident VTE cases and 16,936 controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood, were selected as participants in a previous genome-wide association study (GWAS), and completed a biennial questionnaire at time of blood draw. We selected SNPs that were associated with VTE risk in previous GWAS studies. A genetic risk score (GRS) was constructed to evaluate the combined effect of the 16 SNPs that have reached genome-wide significance in previous GWAS of VTE. Interactions between SNPs and VTE risk factors (BMI and smoking) were also assessed. We found a significant association between our GRS and VTE risk. The risk of VTE among individuals in the highest GRS tertile was 2.02 times that of individuals in the lowest GRS tertile (p-trend = 9.69x10-19). The OR was 1.52 (p=1.03x10-8) for participants in the highest GRS tertile compared to those in the medium GRS tertile. However, while BMI and smoking were associated with VTE, and their effects were additive to each other we did not observe any significant multiplicative gene-environment interactions.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Sexual Differences in Genetic Predisposition of Coronary Artery Disease

2020 ◽  
Author(s):  
Yunfeng Huang ◽  
Qin Hui ◽  
Marta Gwinn ◽  
Yi-Juan Hu ◽  
Arshed A. Quyyumi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Men And Women ◽  
High Genetic Risk ◽  
Genome Wide ◽  
Artery Disease

Background - The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score of CAD. Methods - Using data from the UK Biobank, we constructed a CAD genetic risk score based on all known loci, three mediating trait-based (blood pressure, lipids, body mass index) sub-scores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317,509 unrelated individuals of European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive genetic risk score. Results - For both prevalent and incident CAD, the associations of comprehensive and genome-wide genetic risk scores were stronger among men than women. Using a score of 161 loci, we observed a 2.4 times higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk, but an 80 percent greater risk comparing women with high genetic risk to women with low genetic risk. (interaction p=0.002). Of the three sub-scores, the blood pressure-associated sub-score exhibited sex differences (interaction p=0.0004 per SD increase in sub-score). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11 . Conclusions - Sexual differences in genetic predisposition should be considered in future studies of coronary artery disease, and genetic risk scores should not be assumed to perform equally well in men and women.

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