The CXCR6/CXCL16 axis links inflamm-aging to disease severity in COVID-19 patients

AbstractAdvancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+ T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing the CXCR6 gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+ T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

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Genetic Determinants of Paget’s Disease of Bone

Current Osteoporosis Reports ◽

10.1007/s11914-021-00676-w ◽

2021 ◽

Author(s):

Navnit S. Makaram ◽

Stuart H. Ralston

Keyword(s):

Genetic Factors ◽

Association Studies ◽

Paget’S Disease ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Genome Wide Association Studies ◽

Paget's Disease Of Bone ◽

Genome Wide ◽

Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

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Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽

10.1161/strokeaha.121.032616 ◽

2021 ◽

Author(s):

Martin Dichgans ◽

Nathalie Beaufort ◽

Stephanie Debette ◽

Christopher D. Anderson

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Clinical Applications ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Neuroprotective Agents ◽

Experimental Systems ◽

Genome Wide ◽

Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

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Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2020-26-5-490-500 ◽

2020 ◽

Vol 26 (5) ◽

pp. 490-500

Author(s):

A. O. Konradi

Keyword(s):

Candidate Genes ◽

High Performance ◽

New Technologies ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Modern Approach ◽

Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

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Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

Clinical Science ◽

10.1042/cs20201033 ◽

2021 ◽

Vol 135 (15) ◽

pp. 1929-1944

Author(s):

Ezekiel Gonzalez-Fernandez ◽

Yedan Liu ◽

Alexander P. Auchus ◽

Fan Fan ◽

Richard J. Roman

Keyword(s):

Cognitive Impairment ◽

Association Studies ◽

Amyloid Β ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Cerebrovascular Risk ◽

Potent Vasoconstrictor ◽

Multiple Drugs ◽

Epidemiology Studies

Abstract The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

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Heritability jointly explained by host genotype and microbiome: will improve traits prediction?

Briefings in Bioinformatics ◽

10.1093/bib/bbaa175 ◽

2020 ◽

Author(s):

Denis Awany ◽

Emile R Chimusa

Keyword(s):

Genetic Variants ◽

Association Studies ◽

Heritability Estimate ◽

Substantial Part ◽

Phenotypic Variance ◽

Genome Wide Association Studies ◽

Host Genotype ◽

Genome Wide ◽

Heritability Estimation

Abstract As we observe the $70$th anniversary of the publication by Robertson that formalized the notion of ‘heritability’, geneticists remain puzzled by the problem of missing/hidden heritability, where heritability estimates from genome-wide association studies (GWASs) fall short of that from twin-based studies. Many possible explanations have been offered for this discrepancy, including existence of genetic variants poorly captured by existing arrays, dominance, epistasis and unaccounted-for environmental factors; albeit these remain controversial. We believe a substantial part of this problem could be solved or better understood by incorporating the host’s microbiota information in the GWAS model for heritability estimation and may also increase human traits prediction for clinical utility. This is because, despite empirical observations such as (i) the intimate role of the microbiome in many complex human phenotypes, (ii) the overlap between genetic variants associated with both microbiome attributes and complex diseases and (iii) the existence of heritable bacterial taxa, current GWAS models for heritability estimate do not take into account the contributory role of the microbiome. Furthermore, heritability estimate from twin-based studies does not discern microbiome component of the observed total phenotypic variance. Here, we summarize the concept of heritability in GWAS and microbiome-wide association studies, focusing on its estimation, from a statistical genetics perspective. We then discuss a possible statistical method to incorporate the microbiome in the estimation of heritability in host GWAS.

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Polygenic Susceptibility of Aortic Aneurysms Associates to the Diameter of the Aneurysm Sac: the Aneurysm-Express Biobank Cohort

Scientific Reports ◽

10.1038/s41598-019-56230-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Constance J. H. C. M. van Laarhoven ◽

Jessica van Setten ◽

Joost A. van Herwaarden ◽

Gerard Pasterkamp ◽

Dominique P. V. de Kleijn ◽

...

Keyword(s):

Genetic Risk ◽

Association Studies ◽

Significant Risk ◽

Aortic Aneurysms ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Risk Variants ◽

Genome Wide ◽

Best Fit ◽

Genetic Risk Variants

AbstractRecent genome-wide association studies (GWAS) have discovered ten genetic risk variants for abdominal aortic aneurysms (AAA). To what extent these genetic variants contribute to the pathology of aneurysms is yet unknown. The present study aims to investigate whether genetic risk variants are associated with three clinical features: diameter of aneurysm sac, type of artery and aneurysm related-symptoms in aortic and peripheral aneurysm patients. Aneurysm tissue of 415 patients included in the Aneurysm-Express biobank was used. A best-fit polygenic risk score (PRS) based on previous GWAS effect estimates was modeled for each clinical phenotype. The best-fit PRS (including 272 variants at PT = 0.01015) showed a significant correlation with aneurysm diameter (R2 = 0.019, p = 0.001). No polygenic association was found with clinical symptoms or artery type. In addition, the ten genome-wide significant risk variants for AAA were tested individually, but no associations were observed with any of the clinical phenotypes. All models were corrected for confounders and data was normalized. In conclusion, a weighted PRS of AAA susceptibility explained 1.9% of the phenotypic variation (p = 0.001) in diameter in aneurysm patients. Given our limited sample size, future biobank collaborations need to confirm a potential causal role of susceptibility variants on aneurysmal disease initiation and progression.

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Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Journal of Clinical Medicine ◽

10.3390/jcm9041096 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1096

Author(s):

Jessica Gambardella ◽

Angela Lombardi ◽

Marco Bruno Morelli ◽

John Ferrara ◽

Gaetano Santulli

Keyword(s):

Human Disease ◽

Calcium Release ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genome Wide ◽

Inositol 1,4,5 Trisphosphate ◽

Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

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Role of Bioinformatics in Genome-wide Association Studies

Encyclopedia of Life Sciences ◽

10.1002/9780470015902.a0023578 ◽

2011 ◽

Author(s):

Diane Gilbert-Diamond ◽

Folkert W Asselbergs ◽

Scott M Williams ◽

Jason H Moore

Keyword(s):

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213093 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1078-1084 ◽

Cited By ~ 10

Author(s):

Yong-Fei Wang ◽

Yan Zhang ◽

Zhengwei Zhu ◽

Ting-You Wang ◽

David L Morris ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Fine Mapping ◽

Lupus Erythematosus ◽

Drug Repositioning ◽

Association Studies ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Genome Wide ◽

Causal Variants

ObjectivesSystemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.MethodsWe conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.ResultsWe identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.ConclusionThis study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

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