DNA Methylation and Gene Expression Profiling Reveal
            <i>MFAP5</i>
            as a Regulatory Driver of Extracellular Matrix Remodeling in Varicose Vein Disease

Сметанина, М. А.; Kel, Alexander; Sevost'ianova, Ksenia S; Maiborodin, I. V.; Шевела, А. И.; Золотухин, И. А.; Stegmaier, Philip; Филипенко, М. Л.

doi:10.2217/epi-2018-0001

Cited by 22 publications

(24 citation statements)

References 65 publications

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“…Its product is involved in the inflammatory response in the vascular wall, stimulating the production of the chemokine MCP-1 (Satonaka et al, 2004), which is consistent with the modern view of the pathogenesis of chronic venous disease (Lim, Davies, 2009;del Rio Solá et al, 2009). Additionally, Smetanina and co-workers demonstrated enhanced PPP3R1 expression in VV specimens compared to unaffected veins (Smetanina et al, 2018). In addition to gene prioritization, SMR-HEIDI was used to search for traits associated with VV-related functional variants.…”

supporting

confidence: 54%

The GWAS-MAP platform for aggregation of results of genome-wide association studies and the GWAS-MAP|homo database of 70 billion genetic associations of human traits

et al. 2020

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Hundreds of genome-wide association studies (GWAS) of human traits are performed each year. The results of GWAS are often published in the form of summary statistics. Information from summary statistics can be used for multiple purposes – from fundamental research in biology and genetics to the search for potential biomarkers and therapeutic targets. While the amount of GWAS summary statistics collected by the scientific community is rapidly increasing, the use of this data is limited by the lack of generally accepted standards. In particular, the researchers who would like to use GWAS summary statistics in their studies have to become aware that the data are scattered across multiple websites, are presented in a variety of formats, and, often, were not quality controlled. Moreover, each available summary statistics analysis tools will ask for data to be presented in their own internal format. To address these issues, we developed GWAS-MAP, a high-throughput platform for aggregating, storing, analyzing, visualizing and providing access to a database of big data that result from region- and genome-wide association studies. The database currently contains information on more than 70 billion associations between genetic variants and human diseases, quantitative traits, and “omics” traits. The GWAS-MAP platform and database can be used for studying the etiology of human diseases, building predictive risk models and finding potential biomarkers and therapeutic interventions. In order to demonstrate a typical application of the platform as an approach for extracting new biological knowledge and establishing mechanistic hypotheses, we analyzed varicose veins, a disease affecting on average every third adult in Russia. The results of analysis confirmed known epidemiologic associations for this disease and led us to propose a hypothesis that increased levels of MICB and CD209 proteins in human plasma may increase susceptibility to varicose veins.

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confidence: 54%

The GWAS-MAP platform for aggregation of results of genome-wide association studies and the GWAS-MAP|homo database of 70 billion genetic associations of human traits

et al. 2020

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“…In particular, it induces MCP-1 production, which was shown to be enhanced in VVs 55 , 56 . Finally, a recent study demonstrated that expression of PPP3R1 is increased in the venous tissue of VVs patients compared with veins of healthy individuals (fold change = 1.5) 57 .…”

Section: Resultsmentioning

confidence: 90%

Varicose veins of lower extremities: insights from the first large-scale genetic study

Shadrina

Sharapov

Shashkova

et al. 2018

Preprint

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27Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. 28Genetic factors underlying VVs development remain largely unknown. Here we report the first 29 large-scale study of VVs performed on a freely available genetic data of 408,455 European-30 ancestry individuals. We identified 7 reliably associated loci that explain 10% of the SNP-based 31 heritability, and prioritized the most likely causal genes CASZ1, PPP3R1, EBF1, STIM2, and 32 HFE. Genetic correlation analysis confirmed known epidemiological associations and found 33 genetic overlap with various traits including fluid intelligence score, educational attainment, 34 smoking, and pain. Finally, we observed causal effects of height, weight, both fat and fat-free 35 mass, and plasma levels of MICB and CD209 proteins. 36All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/368365 doi: bioRxiv preprint first posted online Jul. 13, 2018; 3 Varicose veins (VVs) are one of the clinical manifestations of chronic venous disease 37 posing both a cosmetic and medical problem. VVs can be found in different parts of the body, 38 but most commonly occur in the lower extremities. Prevalence estimates of this condition vary 39 across ethnic groups ranging from 2-4% in the Northern group of the Cook Islands to 50-60% in 40 some countries of the Western world 1 The cumulative evidence from epidemiological, family, and genetic association studies 52 strongly indicates that there is a hereditary component in VVs etiology [6][7][8] . However, despite 53 progress in this field [9][10][11][12] , current knowledge of the genetic basis of this pathology is far from 54 being complete. Elucidating genes involved in susceptibility to VVs would help to identify key 55 molecular players in the disease initiation, provide deeper insights into its pathogenesis, and 56 eventually contribute to development of improved targeted therapy aimed at VVs treating and 57 preventing. 58Large-scale biobanks linked to electronic health records open up unparalleled opportunities 59 to investigate the genetics of complex traits. Today, UK Biobank is the largest repository that 60 contains information on genotypes and phenotypes for half a million participating individuals 13 . 61This resource is open to all bona fide researchers, and access to data is provided upon approval 62All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/368365 doi: bioRxiv preprint first posted online Jul. 13, 2018; 4 of their application and payment of necessary costs. However, the need to incur high costs 63 related to data access and computation can be an insurmountable obstacle for those...

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“…In particular, it induces MCP-1 production, which was shown to be enhanced in VVs [28, 29]. Finally, a recent study demonstrated that expression of PPP3R1 is increased in the varicose veins as compared to normal veins (fold change = 1.5) [30]. For the locus on chromosome 16, literature data along with DEPICT analysis strongly suggest the involvement of the PIEZO1 gene.…”

Section: Resultsmentioning

confidence: 99%

Varicose veins of lower extremities: Insights from the first large-scale genetic study

et al. 2019

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Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified the 12 reliably associated loci that explain 13% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1 , PIEZO1 , PPP3R1 , EBF1 , STIM2 , HFE , GATA2 , NFATC2 , and SOX9 . VVs-associated variants within these loci exhibited pleiotropic effects on several phenotypes including blood pressure/hypertension and blood cell traits. Gene set enrichment analysis revealed gene categories related to abnormal vasculogenesis. Genetic correlation analysis confirmed known epidemiological associations between VVs and deep venous thrombosis, weight, rough labor, and standing job, and found a genetic overlap with multiple traits that have not been previously suspected to share common genetic background with VVs. These traits included educational attainment, fluid intelligence and prospective memory scores, walking pace (negative correlation with VVs), smoking, height, number of operations, pain, and gonarthrosis (positive correlation with VVs). Finally, Mendelian randomization analysis provided evidence for causal effects of plasma levels of MICB and CD209 proteins, and anthropometric traits such as waist and hip circumference, height, weight, and both fat and fat-free mass. Our results provide novel insight into both VVs genetics and etiology. The revealed genes and proteins can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets.

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DNA Methylation and Gene Expression Profiling Reveal MFAP5 as a Regulatory Driver of Extracellular Matrix Remodeling in Varicose Vein Disease

Abstract: A coherent model proposed incorporates the relevant signaling networks and will hopefully aid further studies on varicose vein pathogenesis.

Cited by 22 publications

References 65 publications

The GWAS-MAP platform for aggregation of results of genome-wide association studies and the GWAS-MAP|homo database of 70 billion genetic associations of human traits

The GWAS-MAP platform for aggregation of results of genome-wide association studies and the GWAS-MAP|homo database of 70 billion genetic associations of human traits

Varicose veins of lower extremities: insights from the first large-scale genetic study

Varicose veins of lower extremities: Insights from the first large-scale genetic study

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