MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor’s Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p < 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50–3.34, p = 8.77 × 10−5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10−8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09–1.33, p = 4.34 × 10−14 in the weighted analysis).

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Sex Differences in Fluorouracil-Induced Stomatitis

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.2.412 ◽

2000 ◽

Vol 18 (2) ◽

pp. 412-412 ◽

Cited By ~ 42

Author(s):

Jeff A. Sloan ◽

Charles L. Loprinzi ◽

Paul J. Novotny ◽

Scott Okuno ◽

Suresh Nair ◽

...

Keyword(s):

Logistic Regression ◽

Cross Validation ◽

Meta Analysis ◽

Ordinal Scale ◽

North Central ◽

Regression Modelling ◽

Weighted Analysis ◽

Grade 3 ◽

Using Data ◽

Toxicity Criteria

PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)–based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis. PATIENTS AND METHODS: Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation. RESULTS: Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P = .002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P = .0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P < .00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade ≥ 1, (70% v 59%, respectively; P < .00001) and grade 3+ (18% v 11%, respectively; P = .004). CONCLUSION: More women than men reported 5-FU–induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.

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Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

10.1101/2021.12.01.21267132 ◽

2021 ◽

Author(s):

Kazuyoshi Ishigaki ◽

Saori Sakaue ◽

Chikashi Terao ◽

Yang Luo ◽

Kyuto Sonehara ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Association Study ◽

Fine Mapping ◽

Large Scale ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genetic Research ◽

Genome Wide Association ◽

Polygenic Risk Score ◽

Genome Wide

AbstractTrans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.

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Genetic variants associated with platelet count are predictive of human disease and physiological markers

Communications Biology ◽

10.1038/s42003-021-02642-9 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Evgenia Mikaelsdottir ◽

Gudmar Thorleifsson ◽

Lilja Stefansdottir ◽

Gisli Halldorsson ◽

Jon K. Sigurdsson ◽

...

Keyword(s):

Platelet Count ◽

Blood Cells ◽

Myeloproliferative Neoplasms ◽

Meta Analysis ◽

Polygenic Risk Score ◽

Prostate Hyperplasia ◽

Polygenic Risk ◽

Liver And Kidney ◽

Trait Locus ◽

Using Data

AbstractPlatelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

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Trans-ancestry genome-wide analysis of atrial fibrillation provides new insights into disease biology and enables polygenic prediction of cardioembolic risk

10.1101/2021.09.06.21263189 ◽

2021 ◽

Author(s):

Kazuo Miyazawa ◽

Kaoru Ito ◽

Zhaonan Zou ◽

Hiroshi Matsunaga ◽

Satoshi Koyama ◽

...

Keyword(s):

Atrial Fibrillation ◽

Large Scale ◽

Genome Wide Association Study ◽

Rare Variants ◽

Meta Analysis ◽

Polygenic Risk Score ◽

Disease Biology ◽

Genome Wide ◽

Increased Risk ◽

Causal Genes

To understand the genetic underpinnings of atrial fibrillation (AF) in the Japanese population, we performed a large-scale genome-wide association study comprising 9,826 cases of AF among 150,272 individuals and identified five new susceptibility loci, including East Asian-specific rare variants. A trans-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 novel loci. Leveraging gene expression and epigenomic datasets to prioritize putative causal genes and their transcription factors revealed the involvement of IL6R gene and transcription factor ERG besides the known ones. Further, we constructed a polygenic risk score (PRS) for AF, using the trans-ancestry meta-analysis. PRS was associated with an increased risk of long-term cardiovascular and stroke mortality, and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide novel biological and clinical insights into AF genetics and suggest their potential for clinical applications.

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recount: A large-scale resource of analysis-ready RNA-seq expression data

10.1101/068478 ◽

2016 ◽

Cited By ~ 5

Author(s):

Leonardo Collado-Torres ◽

Abhinav Nellore ◽

Kai Kammers ◽

Shannon E. Ellis ◽

Margaret A. Taub ◽

...

Keyword(s):

Large Scale ◽

Meta Analysis ◽

Differential Expression Analysis ◽

Expression Data ◽

Rna Seq ◽

Base Level ◽

Genomic Annotation ◽

Public Data ◽

Using Data ◽

Splice Junctions

Abstractrecount is a resource of processed and summarized expression data spanning nearly 60,000 human RNA-seq samples from the Sequence Read Archive (SRA). The associated recount Bio-conductor package provides a convenient API for querying, downloading, and analyzing the data. Each processed study consists of meta/phenotype data, the expression levels of genes and their underlying exons and splice junctions, and corresponding genomic annotation. We also provide data summarization types for quantifying novel transcribed sequence including base-resolution coverage and potentially unannotated splice junctions. We present workflows illustrating how to use recount to perform differential expression analysis including meta-analysis, annotation-free base-level analysis, and replication of smaller studies using data from larger studies. recount provides a valuable and user-friendly resource of processed RNA-seq datasets to draw additional biological insights from existing public data. The resource is available at https://jhubiostatistics.shinyapps.io/recount/.

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Genetic inhibition of interleukin-6 receptor signaling and Covid-19

10.1101/2020.07.17.20155242 ◽

2020 ◽

Author(s):

Jonas Bovijn ◽

Cecilia M. Lindgren ◽

Michael V. Holmes

Keyword(s):

Lower Risk ◽

Large Scale ◽

Meta Analysis ◽

Population Based ◽

Therapeutic Benefit ◽

Sensitivity Analyses ◽

Control Group ◽

Potential Efficacy ◽

Interleukin 6 Receptor ◽

Using Data

There are few effective therapeutic options for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Early evidence has suggested that IL-6R blockers may confer benefit, particularly in severe coronavirus disease 2019 (Covid-19). We leveraged large-scale human genetic data to investigate whether IL6-R blockade may confer therapeutic benefit in Covid-19. A genetic instrument consisting of seven genetic variants in or close to IL6R was recently shown to be linked to altered levels of c-reactive protein (CRP), fibrinogen, circulating IL-6 and soluble IL-6R, concordant to known effects of pharmacological IL-6R blockade. We investigated the effect of these IL6R variants on risk of hospitalization for Covid-19 and other SARS-CoV-2-related outcomes using data from The Covid-19 Host Genetics Initiative. The IL6R variants were strongly associated with serum CRP levels in UK Biobank. Meta-analysis of scaled estimates revealed a lower risk of rheumatoid arthritis (OR 0.93 per 0.1 SD lower CRP, 95% CI, 0.90-0.96, P = 9.5 × 10-7), recapitulating this established indication for IL-6R blockers (e.g. tocilizumab and sarilumab). The IL-6R instrument was associated with lower risk of hospitalization for Covid-19 (OR 0.88 per 0.1 SD lower CRP, 95% CI, 0.78-0.99, P = 0.03). We found a consistent association when using a population-based control group (i.e. all non-cases; OR 0.91 per 0.1 SD lower CRP, 95% CI, 0.87-0.96, P = 4.9 × 10-4). Evaluation of further SARS-CoV-2-related outcomes suggested association with risk of SARS-CoV-2 infection, with no evidence of association with Covid-19 complicated by death or requiring respiratory support. We performed several sensitivity analyses to evaluate the robustness of our findings. Our results serve as genetic evidence for the potential efficacy of IL-6R blockade in Covid-19. Ongoing large-scale RCTs of IL-6R blockers will be instrumental in identifying the settings, including stage of disease, in which these agents may be effective.

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Epidemic size of novel coronavirus-infected pneumonia in the Epicenter Wuhan: using data of five-countries’ evacuation action

10.1101/2020.02.12.20022285 ◽

2020 ◽

Cited By ~ 6

Author(s):

Hongxin Zhao ◽

Sailimai Man ◽

Bo Wang ◽

Yi Ning

Keyword(s):

Public Health ◽

Infection Rate ◽

Large Scale ◽

Meta Analysis ◽

Random Effect ◽

Random Effect Model ◽

Population Mobility ◽

Epidemic Size ◽

Using Data ◽

Novel Coronavirus

AbstractBackgroundSince late December 2019, novel coronavirus–infected pneumonia (NCP) emerged in Wuhan, Hubei province, China. Meanwhile, NCP rapidly spread from China to other countries, and several countries’ government rush to evacuate their citizens from Wuhan. We analyzed the infection rate of the evacuees and extrapolated the results in Wuhan’s NCP incidence estimation.MethodsWe collected the total number and confirmed cases of 2019-nCov infection in the evacuation of Korea, Japan, Germany, Singapore, and France and estimated the infection rate of the 2019 novel coronavirus (2019-nCov) among people who were evacuated from Wuhan with a meta-analysis. NCP incidence of Wuhan was indirectly estimated based on data of evacuation.ResultsFrom Jan 29 to Feb 2, 2020, 1916 people have been evacuated from Wuhan, among them 17 have been confirmed 2019-nCov infected. The infection rate is estimated to be 1.1% (95% CI 0.4%-3.1%) using one group meta-analysis method with random effect model. We then estimated that almost 110,000 (95% CI: 40,000-310,000) people were infected with 2019-nCov in Wuhan around Feb 2, 2020, assuming the infection risk of evacuees is close to Chinese citizens in Wuhan.ConclusionsAt the beginning of the outbreak, incidence of NCP may be vastly underestimated. Our result emphasizes that 2019-nCov has proposed a huge public health threats in Wuhan. We need to respond more rapidly, take large-scale public health interventions and draconian measures to limiting population mobility and control the epidemic.

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Population-specific and transethnic genome-wide analyses reveal distinct and shared genetic risks of coronary artery disease

10.1101/827550 ◽

2019 ◽

Author(s):

Satoshi Koyama ◽

Kaoru Ito ◽

Chikashi Terao ◽

Masato Akiyama ◽

Momoko Horikoshi ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cardiovascular Mortality ◽

Large Scale ◽

Meta Analysis ◽

Genotype Imputation ◽

Polygenic Risk Score ◽

Genome Wide ◽

Increased Risk ◽

Artery Disease

AbstractTo elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.

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A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-209436 ◽

2016 ◽

Vol 76 (1) ◽

pp. 286-294 ◽

Cited By ~ 30

Author(s):

Ana Márquez ◽

Laura Vidal-Bralo ◽

Luis Rodríguez-Rodríguez ◽

Miguel A González-Gay ◽

Alejandro Balsa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Meta Analysis ◽

Polygenic Risk Score ◽

Type I ◽

Systemic Lupus ◽

Genome Wide ◽

Genetic Overlap

ObjectivesDuring the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE.MethodsWe performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls.ResultsThe rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E−13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein–protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE.ConclusionsIn conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.

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Relationship between total plasma homocysteine and the risk of aneurysms – a meta-analysis

VASA ◽

10.1024/0301-1526/a000891 ◽

2020 ◽

pp. 1-6

Author(s):

Hanji Zhang ◽

Dexin Yin ◽

Yue Zhao ◽

Yezhou Li ◽

Dejiang Yao ◽

...

Keyword(s):

Large Scale ◽

Meta Analysis ◽

Single Species ◽

Total Plasma ◽

Control Groups ◽

Randomized Controlled ◽

Randomized Controlled Studies ◽

The Difference ◽

The Relationship ◽

Healthy Participants

Summary: Our meta-analysis focused on the relationship between homocysteine (Hcy) level and the incidence of aneurysms and looked at the relationship between smoking, hypertension and aneurysms. A systematic literature search of Pubmed, Web of Science, and Embase databases (up to March 31, 2020) resulted in the identification of 19 studies, including 2,629 aneurysm patients and 6,497 healthy participants. Combined analysis of the included studies showed that number of smoking, hypertension and hyperhomocysteinemia (HHcy) in aneurysm patients was higher than that in the control groups, and the total plasma Hcy level in aneurysm patients was also higher. These findings suggest that smoking, hypertension and HHcy may be risk factors for the development and progression of aneurysms. Although the heterogeneity of meta-analysis was significant, it was found that the heterogeneity might come from the difference between race and disease species through subgroup analysis. Large-scale randomized controlled studies of single species and single disease species are needed in the future to supplement the accuracy of the results.

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