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Page 6 of 13 Smetanina et al. Vessel Plus 2021;5:19 https://dx.doi.org/10.20517/2574-1209.2021.17

underlying the disease. Particularly in VVD, the following genes are subjected to hypermethylation: ADCY3,
DPEP2, HRC, PLXNB1 and MFAP5 [30,31] . Hypomethylation of the CCN5 (WISP2) gene in VVs [30,32] induces
its activity, which, in turn, potentiates TGF-β. The result is the remodeling of the extracellular matrix.
Moreover, changes in DNA methylation at specific loci as well as other epigenetic marks (histone
modifications and non-coding RNAs) are heritable [33,34] . For instance, it was demonstrated that genetically
identical mice may differ in the degree of their tails’ kinkiness, so that mysterious epigenetic marks
responsible for variable expressivity are inherited between generations .
[35]

Our study using large-scale microarray analysis of transcriptome and methylome identified sets of
differentially expressed genes and differentially methylated DNA loci in VVs compared to non-varicose
[30]
veins . Using independent methods and replicative sample sets, we already validated some of these data.
By dint of bioinformatics analysis performed by our colleagues from Germany, the relationship of such
master regulators was shown, i.e., those genes whose products are likely to participate in the pathogenesis
and possibly trigger the processes of vein wall remodeling and its varicose transformation. These are genes
for the extracellular matrix organization (including collagens and tissue inhibitors of metalloproteinases),
cell adhesion and vascular morphogenesis. Figure 1 schematically represents (of course, not completely) the
interplay of the genetic master regulators contributing to VVD development.

WHERE ARE WE NOW IN TERMS OF LEARNING, IN TERMS OF UNDERSTANDING, AND
WHERE ARE WE GOING? A CHALLENGE FOR THE FUTURE
Molecular events occurring in the pathogenesis of VVs are indeed known fragmentarily, and their sequence
is not always clear: what is the cause and what is the consequence. Many of the heroes involved in certain
events are still behind the scenes. By studying the features of gene expression and methylation in the
pathological condition, as well as other processes, researchers are able to decipher the mechanisms and
various stages of pathogenesis step by step.

Realizing that, after all, the pathogenesis of chronic venous diseases is a very complex process, it should be
borne in mind that even a single gene effect can cause little influence. Therefore, studies with a large
number of patients are required before drawing any conclusions. In addition, the impact of a particular
polymorphism will depend on genotype-environment interactions that may be specific to a given patient
population. Genome-wide research has indeed made a significant contribution to the discovery of genes
associated with venous pathology, but there are still puzzles that need to be pieced together. Multicenter
international studies and the formation of consortia will help to clarify the connection between genetic
markers and various pathological components of chronic venous diseases, including VVD. When efforts
come together, these will not only be large samples, but they will also be synchronized according to
inclusion-exclusion criteria, research methodology and interpretation of the analysis results, and they will
take into account the ethnicity of the analyzed groups.

It is expedient to draw the attention of readers to the following fact: the absence of the relative levels of
genes’ expression in the veins in relation to other organs and tissues. In one of the largest databases of
biological and medical research, NCBI (PubMed/Gene), there is no information on the levels of gene
expression, not only in the veins but even in the vessels! Only 27 organs and tissues are indicated there
(heart, lungs, liver, kidneys, etc.). In another database-UCSC Genome Browser on human-which provides
the gene expression profiles in 54 organs and tissues, one can already find information on gene expression
in the arteries (however, only in three kinds-aorta, coronary and tibial arteries), but the veins are not there
yet. If we imagine it is possible to add new missing data, then in perhaps the future it will be possible to get a
more complete picture. Of course, such voluminous studies on large samples of people require large