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Smetanina et al. Vessel Plus 2021;5:19 https://dx.doi.org/10.20517/2574-1209.2021.17 Page 5 of 13

the SNP-based heritability of VVs, prioritizing the most likely causal genes (shown in brackets): rs11121615
(CASZ1), rs2911463 (PIEZO1, CTU2), rs2861819 (PPP3R1, PNO1), rs3101725 (SLC12A2, FBN2,
LINC01184), rs11135046 (EBF1), rs28558138 (STIM2), rs7773004 (HFE), rs12625547 (NFATC2), rs2241173
[SOX9, AC005152.3 (LOC102723505)], rs73107980 [COL2A1, RAPGEF3 (EPAC1)], rs9880192 (GATA2) and
rs236530 (KCNJ16, KCNJ2) . All of those SNPs are the same as those found by Fukaya et al. , and only
[26]
[27]
the last two are not in the top 30. Thus, the genetic risk factors found in both works broaden the
understanding of VV pathogenesis and can help in further studies to elucidate the mechanisms of the
development of the disease.

GENE EXPRESSION STUDIES ON VARICOSE VEIN PATHOGENESIS-AN OVERVIEW
In addition to genomic studies, one of the ways to “decipher” the possible stages of VV pathogenesis is to
study the features of the expression of certain genes in the pathological condition compared to the normal
condition. Such differentially expressed genes can be involved in the pathogenesis of the disease by
changing the quality of their participation in any functional process or signaling pathway. Common
approaches to the search for differential gene expression are both the candidate gene approach and large-
scale transcriptome analysis, which became possible with the emergence of high-throughput microarray or
RNA sequencing technologies-the so-called “omic” studies. Scrutinized literature analysis of gene
expression studies (including microarray and mRNA-/tRNA-/lncRNA-sequencing approaches) relevant to
VV pathogenesis is presented in two of our works “Differentially expressed genes in varicose vein disease:
[28]
current state of the problem, analysis of the published data” and “Differentially expressed genes in lower
limb varicose vein disease” that complement each other. For example, a change in the expression level of
[29]
the following genes was shown repeatedly (according to the results of more than one scientific work) in
VVD (the arrow direction corresponds to up- or downregulation): ↑ VEGF (VEGFA), ↕ PTGS2 (СОХ2), ↑
BCL2, ↑ BAX, ↑ BNIP3, ↑ HIF1A, ↓ СD31 (PECAM-1), ↑ TGF-β (TGFB1), ↓ TAGLN (SM22-alpha), ↑ miR-202
(microRNA 202), ↓ CXCL8 (IL8), ↑ SEPP1 (SELENOP), ↑ RGS4, ↓ FOS (p55, AP-1, C-FOS), ↓ SOD2 (
Mn-SOD), ↓ VCL, ↑ ACTC1, ↑ TMEM158 (RIS1), ↑ COL15A1, ↑ CHRDL2, ↑ EFEMP1 and ↑ TIMP1.
Therefore, these data can be considered reliable. It can be observed that among them are growth factors and
mitochondrial proteins, including those involved in apoptosis. Proteins that belong to the extracellular
matrix group play an essential role in varicose transformation of the venous wall. It is worth noting that our
works also have made a significant contribution to all of this research.

Since the phenotype of a cell or organism as a whole depends on variable gene expressivity, inheritance of
the transcriptional status of genes can lead to epigenetic effects. An essential role in the regulation of gene
expression is played by epigenetic mechanisms, which include interactions between genetic variants and
environmental factors, cellular reactions and pathological processes. DNA methylation is an epigenetic
modification that occurs by attaching a methyl (CH ) group to the cytosine bases of DNA without changing
3
its sequence, thereby often changing the expression of genes and affecting their function. If we imagine this
figuratively in the form of two clothed hands, then, in the case when there is a methyl group, it is a mitten,
and, in the absence of it, it is a glove that allows fingers to freely interact (having shown its activity) with
transcription factors and the entire transcriptional machine for further regulation of gene expression. In the
case of cytosine methylation within the CpG loci, especially if they are concentrated in the regulatory
regions of the genome, such as promoters (proximal or distal) or enhancers, “gene shutdown” occurs, i.e.,
suppression of transcription. In the opposite case, if such a CpG locus is not methylated, then the gene is
“turned on”, i.e., it is transcribed; therefore, mRNA from this gene is produced and the protein is also
translated (synthesized) in the cell. Hyper- or hypomethylation can cause both inactivation and
autoactivation of genes. If the process affects suppressor genes, then the result is the activation of normally
suppressed processes. This can serve as a powerful tool for understanding the molecular mechanisms