Genetics in chronic venous disease

Chronic venous disease (CVD) is highly prevalent in the Western world, with varicose veins being the most common form of clinical manifestation. ¹ A number of environmental risk factors have been attributed to the development of varicose veins including age, raised body mass index and pregnancy. ² However, many patients exposed to these risk factors do not develop the disease and primary varicose veins are also seen in young adults with no specific cause. It is well recognized that CVD runs in families, nevertheless, the genetic basis for this connection is yet to be elucidated.

With recent advances in sequencing technology, scientists and clinicians alike have arrived at a particularly useful vantage point to enquire into the genetic susceptibility of CVD. ³ Pursuing a genome-wide frontier has the potential to reveal novel critical metabolic pathways involved in primary varicose veins and may translate into improved disease prevention or treatment, which would benefit patients suffering from the clinical sequelae of CVD. For example, application of the underlying biogenetics could permit an improved ability to predict which patients will develop CVD and encourage attempts at therapeutic modulation. The use of a specific molecular pharmaceutical agent may allow targeted inhibition of structures of proven pathogenetic relevance, rather than depending on trial and error with phlebotonic drugs of unknown efficiency.

Familial studies have been paramount in the determination of familial risk and heritability of CVD. Regrettably, there is extensive variation in the cited prevalence in patients with positive family history.^4,5 Despite the demonstration of familial aggregation and clustering of the varicose vein phenotype, these small-scale, single-centre studies have displayed widespread disparity with no accurate estimate of heritability in the general population. The genes involved in primary venous failure remain elusive and the magnitude of genetic contribution to the disease phenotype has yet to be clarified.

The methods being taken to identify genes involved in CVD include analysis of heredity by familial studies, differential gene expression studies, individual candidate gene approaches or casting the net more widely throughout the whole genome. ³ It is of interest that a number of gene expression studies have now identified up-regulation of extracellular matrix components and cytoskeletal proteins in CVD. ⁶ However, these findings are suggestive of pathological response to injury and subsequent repair. Future interrogation of the implicated genes must place an emphasis on the aetiological process of CVD in order to address this predicament. To complicate matters further, temporal fluctuations and epigenetic nuances of local gene expression can significantly alter mRNA levels, limiting gene expression studies as a tool. ³

A hypothesis-driven approach utilizing candidate gene studies may present a more sensible approach to cracking the genotypic puzzle associated with CVD. FoxC2 gene was realized to be responsible for the rare inherited condition of lymphedema distichiasis in 2002. ⁷ A recent study postulated that the presence of the c.512C > T polymorphism may trigger an altered FoxC2-Notch signaling cascade, resulting in remodeling of saphenous vein in patients with CVD. ⁸ Notwithstanding recommendation in the literature that studies ‘should contain an initial study as well as an independent replication’, ⁹ there have been no advances confirming an association of FoxC2 with primary varicose vein disease. Thrombomodulin, an endothelial cell surface glycoprotein receptor for thrombin, has also been allied to the development of CVD. In another candidate gene study, 19% of the cases with the del TT allele mutation of thrombomodulin were found to have varicose vein disease. ¹⁰ However, the study failed to identify prudent risk factor information for varicose veins; therefore, the distribution of del TT allele in the controls was not available due to the a posteriori study design.

The emergence of responsible genetic factors in the development of CVD is promising, but necessitates further in-depth work in order to validate the existing evidence. There has been a general failure to produce reproducible results in independent cohorts with many studies differing in their definition of the disease phenotype and lacking meticulous characterization of the study groups. In a twin cohort study comparing the incidence of varicose veins and haemorrhoids to a candidate chromosome marker, the phenotype was obtained from a self-administered questionnaire. Conversely, another study used venous duplex scan, while some based their definition on clinical examination. ³

If gene expression studies and candidate gene studies provide barriers, genome-wide association studies (GWAS) may be the more addressable candidate. GWAS involve the direct genotyping of common genetic variants, usually single nucleotide polymorphisms (SNPs), in hundreds to thousands of DNA samples using microarray technology. ³ Algorithms are utilized which compare the frequency of SNPs between disease and control cohorts, based on the premise that adjacent parts of the chromosome are inherited together with a disease-influencing allele. This permits for unbiased investigation of the entire genome for any phenotypic links. So far in, this framework has generated significant enthusiasm in both industrial and academic communities and has uncovered a startling degree of structural genomic variation in conditions such as coronary artery disease and diabetes mellitus. ⁹ An advantage of the GWAS approach would be its potential to identify unsuspected loci, which have not been previously considered due to our limited assumptions of the biological pathways involved in venous disease. ³ But to date, this hypothesis-free directed approach has not been fruitful in a CVD or varicose vein population.

Recent efforts have scratched the surface of the genetic inquiry into CVD, yet the secrets of true association remain out of reach. Clearly, efforts must not be wasted on poorly designed studies and inappropriate means of analysis. ⁹ The emergence of high-throughput genotyping platforms permits a more systematic search for inherited components of CVD. Three years ago, the editors noted an atmosphere of confusion surrounding the precise genetic factors involved in the development of CVD, ³ despite a large body of circumstantial evidence implicating their presence. Researchers should be urged to foster collaborative links and design a genome-wide association study as an international consortium to provide a statistically robust paradigm in the field of CVD genetics. This will carry promise for clinically relevant progress and represent a first step towards better understanding of the aetiology of CVD.