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Smetanina et al. Vessel Plus 2021;5:19 https://dx.doi.org/10.20517/2574-1209.2021.17 Page 3 of 13

GENETIC ASSOCIATION STUDIES ON VARICOSE VEIN PATHOGENESIS-AN OVERVIEW
At the initial stages of the interaction of genetics and phlebology, associative studies of the “case-control”
type were carried out, i.e., when the hypothesis is tested whether a genetic marker is found more often in a
group of patients than in a control group. Originally, a gene-candidate approach was used, i.e., when one
gene or a group of genes was selected, which can participate in the manifestation of some trait with a high
probability. These genes were studied using genetic methods known at that time, and many of the studies
reviewed provide conflicting data on the clinical significance of genetic associations. In particular, there are
several distorting factors that make it difficult to compare between studies. There are different criteria for
inclusion and exclusion, subjectivity in diagnosis, the presence of comorbidities, different sources of control
groups, size disparity between the groups and differences between ethnic groups. Our 2016 review “The
genetic base of chronic venous disease: a review of modern concepts”, which is highly scrutinizing from a
genetic point of view, provides the detailed information available at that time about the relationship of
genetic factors with the development of chronic venous disease . Thus, the table “Polymorphic
[12]
variants/mutations of candidate genes and their associations with chronic venous disease” shows not only
the gene, the type of mutation/single nucleotide polymorphism (SNP) and the reference to the article, but
also the sample size and the degree of this association, which is decisive for the significance of this
association. In the studies performed in our laboratory, it has been shown that, for example, for
polymorphic variants of genes AGGF1 (rs13155212, rs7704267) , MTHFR (rs1801133) and MTR
[13]
(rs1805087) , no associations with the risk of VVD in ethnic Russians were found. There were also no
[14]
associations found for regulatory SNPs of matrix metalloproteinase genes MMP1 (rs1799750), MMP2
[15]
(rs243865), MMP3 (rs3025058) and MMP7 (rs11568818) , whereas the rare rs1800562 A allele in the HFE
gene leading to the accumulation of iron in the patient’s tissues and polymorphic variants rs1035550 C>T
[16]
and rs34221221 T>C of the transcription factor FOXC2 gene were associated with an increased risk of
[17]
VVD. However, none of these associations reached statistical significance after adjustment for multiple
comparisons. For the polymorphic locus rs2010963 G > C in the VEGFA gene for the vascular endothelial
growth factor, an association with a decreased risk of VVD was revealed, and its significance remained after
applying the Bonferroni correction . On the sample of ethnic Russians, we also revealed the association of
[18]
functional SNP rs1024611 in the regulatory region of the MCP1 gene with the increased risk for primary VV
development, which was prominent in C2-class patients, in patients younger than 30 years old at disease
onset and in patients with negative anamnesis . Thus, there was other evidence for an inflammatory
[19]
component implication in the pathogenesis of VVs. Later on, we applied a candidate-gene approach to test
the implication of 13 functional polymorphisms in the inflammation-related genes to VVD and revealed the
association of C allele of the IL6 rs1800795 and the reverse association of T allele of the HIF1A rs11549465,
ATTG deletion of the NFKB1 rs28362491 and A allele of the TNF rs3093661 with an increased risk of
primary VVs . Notwithstanding, the statistical significance level turned insignificant after correction for
[20]
multiple comparisons. However, that study had some limitations; therefore, not all associations could be
false discoveries.

Entering the era of opportunities and thorough screening of the genome, methylome, transcriptome,
proteome, etc., we obtain new unprecedented potential for research on the molecular pathology of venous
diseases using agnostic approaches (i.e., free from the original hypothesis) without the need to focus on
individual genes. Figuratively, the candidate gene and omics approaches for research can be compared with
lighting a street with one lantern or many lanterns, respectively. Obviously, in the latter case, it becomes
much easier to find something on it.

One of the biggest genome-wide association studies (GWASs) on VVs was performed by the American
23andMe company scientists who identified a group of 12 SNPs and genes corresponding to them: rs507666