Various approaches have been used to investigate genetic predisposition to complex diseases, but the most fruitful method has been the study of twins. This was initiated with an earlier study which used the method of discordant twin-pair analysis to calculate a higher trait-specific (as opposed to disease-specific) concordance rate in female monozygotic twins compared to dizygotic twin and same-sex sibling pairs (48% compared to 21% and 16% respectively), indicating a genetic influence on the development of varicose veins. Although no studies on twins specifically to investigate genetic predisposition have been performed, a study of chronic venous insufficiency (a term which encompasses a broad spectrum of venous disease including varicose veins) has demonstrated that a composite genetic and environmental path model is most suitable to explain familial aggregation of this condition. This finding is likely to be applicable to varicose vein.
This is a difficult task because the diagnosis of varicose veins can be subjective and somewhat arbitrary, partly due to the varied and overlapping symptoms of this condition and the fact that it represents the severe end of a spectrum with no clear demarcation from milder forms of venous disease. Also, the biological changes associated with the development of varicose veins occur over many years. Nevertheless, evidence suggests that there is a genetic predisposition to varicose veins, predominantly through familial aggregation studies, has accumulated over the years, but this is the first time that a systematic review has been performed on this topic.
Varicose veins are a frequently encountered condition, affecting 25 to 33% of females and 10 to 20% of males. A wide variation in severity is noted, but those affected are often troubled by symptoms and the unsightly appearance of the condition. The condition incurs substantial financial costs, with much of this relating to loss of time from work. Understanding of the genetic and environmental factors that determine why varicose veins develop and why they are troublesome is poor but is essential for the development of targeted preventative and therapeutic strategies.
Genetic Predispositions and Varicose Veins
The study of genetic predispositions to varicose veins is a relatively new field. The assumption that varicose veins are an inherited disorder is based on the fact that each individual with varicose veins will have a family member who also suffers from the condition. However, this is a woefully unrepresentative measure of the heritability of varicose veins, as is demonstrated by a study by Evans et al. This research concluded that only a third of those with varicose veins had a first-degree relative who experienced similar problems. This is only slightly higher than the average female population, suggesting that genetic predisposition is only a modest component in the development of varicose veins. It is also commented that environmental factors may play a critical role in the progression of varicose veins. This was suggested from the fact that there was considerable variation in occupational leg strain in sets of identical twins, despite the twins tending to have similar patterns of venous abnormalities. The time at which the individuals partake in occupational leg straining activities throughout their life may account for differing venous abnormalities, thus showing that environmental factors and the timing of such factors may actually hold a more significant influence than genetic inheritance.
Inheritance Patterns
The most commonly known inheritance pattern is that of the Dutch type. This is an autosomal dominant pattern that causes symptoms in the second half of life. The disease was first described in 1684 and since then many families have been reported that have the features of the Dutch type. An example of one particular family was thoroughly documented by Hull et al. A family tree from this study is shown in Figure 1. In this particular family, the matriarch (deceased at age 82) had suffered with severe varicose veins for 50 years. Investigation found an extensive history of varicose veins and/or venous ulcers in 20 out of 67 relatives. Clinical assessment showed that 20 of the 67 also had classical or early signs of varicose veins and/or venous ulcers. DNA analysis showed genealogical evidence of a common ancestor. This family shares many characteristics with others reported with the Dutch type and suggests a high penetrance of the gene and a clear genealogical link. Many generations are affected with varying severity of disease and have the classical type of varicose veins with venous ulcers. This has all the hallmarks of an as yet unidentified genetic defect.
There are likely to be a variety of inheritance patterns that are relevant to the genetic predisposition to varicose veins, but it is difficult to ascertain for a condition that is so common in the general population. Varicose veins usually cause symptoms in later life, and as such it is difficult to obtain a clear family history on older generations. The best knowledge of inheritance patterns comes from the Dutch type of varicose veins.
Gene Mutations Associated with Varicose Veins
Another gene mutation that can lead to varicosities involves the gene for forkhead box protein C2 (FOXC2) which is a gene specific for venous valve formation and maintenance. Studies show evidence that FOXC2 is mutated in some patients with varicose veins and it was found that people with a missense mutation of this gene were more likely to develop varicose veins with age, suggesting that FOXC2 gene is imperative in preventing venous reflux and varicose veins. These discoveries have provided an understanding into the genetic causes of varicose veins and may eventually lead to the prevention of this condition in people that have genetic predispositions.
Col1a1 and Col1a2 are genes responsible for coding collagens, which are a major component of the extracellular matrix and the formation of the vein wall. A substitution in the coding sequences of these genes can lead to the production of abnormal collagen molecules, which impairs the strength of the vein wall. also found higher levels of mRNA for part of the Sp1 gene, and also the Sp3 gene. These are regulatory genes which modify the expression of other genes, and heightened levels of these can lead to over-expression of a number of genes. This includes MMPs and integrins, which then cause excessive degeneration of extracellular matrix and the interruption of integrins with the collagen cause a weakened vein wall.
Gene mutations have been a topic of interest regarding the formation of varicose veins. While discussing the causes of varicosities, it was previously mentioned that weakened vein walls and valves can lead to the pooling of blood. These changes can be attributed to mutations in the genes that are responsible for the formation of the venous valves and the venous wall. Studies state that “inflammation, degeneration of extracellular matrix and changes in the vein wall are the pivotal points in the development of varicose veins” (p. 7). During their studies, they found that there were abnormalities in a number of genes expressed by vein walls, that differed from normal veins.
Genetic Risk Factors
Several risk factors are genetic in nature. The risk of developing varicose veins increases if an individual’s relatives, especially their parents, have had them. In fact, the Framingham Study showed that people with a family history of varicose veins were twice as likely to develop them as people without a family history of varicose veins. The inheritance pattern is not completely understood, however. It is believed that varicose veins are a polygenic condition, meaning that many different gene abnormalities combine to produce the condition. It is also believed that varicose veins are a multifactorial condition, in which both genetic and environmental factors combine to produce the condition. This suggests that lifestyle changes aimed at preventing varicose veins may be effective even in people who are genetically predisposed to varicose veins.
Family History and Varicose Veins
An early study conducted in Britain on 3000 men from the same working population demonstrated that varicose veins were present in 23% of those with a positive family history, as compared to 8% in those with a negative history. This was looked at the firefighters who had positive and negative family history, and the risk for varicosities has been calculated to be 1.9 to 2.2, showing that familial factors had a marked effect on susceptibility to varicose veins.
Familial Clustering of Varicose Veins
Family history is a risk factor for the development of varicose veins. This was diagnosed to be present in around 73% of patients with varicose veins, compared with 43% in the control group. In a previous epidemiological investigation, monographs of 88 consecutive patients with varicose veins have revealed that 70 (79.5%) had an aware family history of varicose veins. Their risk was estimated to be a relative of 5.7. It has been claimed that patients who had a known family history of varicose veins were more likely to have earlier symptoms and signs related to venous disease. This suggests that initial venous abnormalities are inherited in varicose veins and the progression is a result of prolonged exposure to factors damaging to the vein.
Importance of Family History
Anecdotal evidence suggests that if one has a parent with varicose veins, then they have a 60% chance of developing them. A study conducted to investigate the validity of this claim found that if a parent has varicose veins, then there is a 90% chance that their child will get them. Genetic epidemiology makes the strong case for a genetic predisposition. The Framingham study found the heritability of varicose veins to be between 70-78%. It stands to reason therefore, that if varicose veins have a high heritability rate, then it is likely that the chances of developing them are also quite high. In comparison to other common conditions such as high blood pressure or heart disease, those with a family history of varicose veins have a much higher relative risk of suffering from the same ailment. For example, you are twice as likely to develop varicose veins if your parents had them. High relative risk combined with high heritability is indicative of a strong genetic association, and when the relative risk is ascertained through large population studies, it can be a useful method in determining whether genetics plays a role in the development of varicose veins. A relative risk can show the strength of the impact of a gene, which can vary between different genes, and genetic association studies are aimed to determine which genes are linked to the development of varicose veins. Although it is known that it is likely a combination of genes rather than a single gene which causes varicose veins, newer studies are beginning to show that polymorphisms of certain genes may increase the susceptibility of developing varicose veins. This information can be useful in the future for determining risk of getting varicose veins before their actual development.
Familial Clustering of Varicose Veins
However, there are limitations to twin studies and although the result strongly indicates a genetic influence, further research is needed to identify specific genes involved.
A study of 3566 sets of Danish twins concluded that varicose veins were more frequent in monozygotic twins (37.9%) than dizygotic twins (23.3%). This result indicated a genetic predisposition and the authors estimated the contribution of genetic effects to be 62%. This is a high figure compared to the genetic influence estimated for other common complex diseases such as 35% for type 2 diabetes.
If monozygotic twins are found to have a significantly higher concordance rate of varicose veins compared to dizygotic twins, it can be inferred that there is a hereditary cause.
The clustering of varicose veins in families has been a much-debated topic. Is the increased occurrence noted in families a result of genetic predisposition or the imitation of parents’ lifestyles? Clarification of this issue would benefit the identification of causes of progression of varicose veins and aid in the development of preventative strategies. Twin studies are a valuable resource in the exploration of genetic influence.
Shared Environmental Factors
At least four studies have assessed specific environmental exposures in relation to varicose veins, with conflicting results. Haughton and Hacking found a higher rate of varicose veins in women living in areas supplied with water from soft water districts in England. A case-control study in Edinburgh found a higher rate of varicose veins in women using water closet toilets as compared with those who used traditional toilets, but this was largely explained by confounding due to council housing; there was no difference in the incidence of varicose veins by type of toilet used after controlling for social class. Two studies focusing on women using hormone replacement therapy (HRT) reported conflicting results: an increased incidence of varicose veins in association with oral HRT in the Nurses Health Study, and an increased incidence of leg vein surgery among HRT users, although no dose-response effect or association with superficial venous reflux was found in the Women’s Health Initiative Study.
Family clusters of varicose veins might also reflect the influence of shared environmental factors on the development of varicose veins. Identification of environmental factors can be confounded by the tendency of individuals from the same family to have similar lifestyles. An environmental influence is supported by the finding that men with occupations that require prolonged standing have an increased incidence of varicose veins. The association is not definitive in all studies, and it is complicated by the fact that occupations involving prolonged standing are also associated with obesity. Women with occupations that involve prolonged standing and those with multiple pregnancies are at increased risk for varicose veins compared with women who do not stand a great deal at work and nulliparous women. In Framingham Heart Study data, strong or often lifting was associated with the incidence of varicose veins or telangiectasias in women, although the association was not statistically significant after controlling for age and obesity. High intensity activities or competitive sports were inversely associated with varicose veins, and an interquartile range increase in systolic blood pressure or pulse rate was associated with a statistically significant 27-28% increased risk of varicose veins or telangiectasias.
Role of Lifestyle and Habits
Several studies have demonstrated strong evidence in the role of lifestyle and certain habits as risk factors. A study based on questionnaire and interview responses by Urban and Jelnes found that more patients with varicose veins than controls smoked at some time in their life. All patients were middle-aged or elderly Danish men. Those with varicose veins were twice as likely to smoke (69%) than the control group (34%). It was also found that men who were heavy smokers (20 cig/day) had more severe changes than light smokers. Another study by Beebe-Dimmer et al. found similar results among a population of American men. Data showed that there was a weak association between current or former smokers and varicose veins among men. Also, smoking 18 or more pack-years was significantly associated with varicose vein occurrence. A graded response was noted with the increasing pack-year exposure. The authors concluded that their study suggested a weak association between smoking and varicose veins. Their findings among pack-year exposure and graded response provide a better understanding of smoking as a risk factor. Recent studies have also shown that there are strong associations with the inflammatory process and smoking. A study by Cheng et al. found that smoking was associated with elevated markers related to inflammation and varicose veins such as elevated leukocyte count, neutrophil count, and low hematocrit. This study demonstrated that these inflammatory effects were dose-related to the amount of smoking which helps support the evidence for smoking as a risk factor and support why there is a graded response. Another inflammatory marker which has been identified is C-reactive protein. High levels of C-reactive protein are a risk factor for venous disease and a study by Shadid and Szeinsky showed that it was elevated in the plasma of varicose vein patients. They also showed that there was a significant increase in skin and plasma neutrophil elastase levels in varicose vein patients. This is significant as another study by Loffredo et al. demonstrated that nicotine patches induced a time- and dose-dependent increase in neutrophil elastase and activation of neutrophils and they stopped shortly after the patch was removed. This provides more support that there is an association with smoking and the activation of neutrophils and nicotine can be a trigger. This research indicates that smoking does indeed appear to be a very important and modifiable risk factor for varicose veins since the inflammatory effects start quickly after and quitting smoking will progressively reduce the risk.
Conclusion
Furthermore, genes have an effect on the risk of developing venous disease and its severity. The genes which code for connective tissue components such as collagen, elastin, and glycosaminoglycans are good candidates as these tissues form the framework of the venous wall and valve cusps. Adducin polymorphisms have also been implicated with venous disease in a French-Canadian population, as has Factor V Leiden in the development of post-thrombotic and other venous disease. The roles of these and other genes in venous disease require further elucidation. The same statement applies to the heritability of varicose veins, CVI, and VLU, and the genetic factors influencing their progression. It is an area where patients could potentially be screened to identify those at risk, and where the identified abnormalities could be rectified or compensated for in some way. However, at present, it is difficult to give more than general advice on familial risk and it is not possible to make specific recommendations regarding gene-based treatment or prevention. High-quality genetic epidemiological studies of familial disease and the identification of relevant genotype will be required to change this situation.
Despite what many people believe, varicose veins are a largely under-researched topic, especially concerning genes and family history. As of yet, there are no commonly agreed-upon methods of diagnosing and grading the severity of varicose veins to facilitate the drawing of firm conclusions. The huge variances in the types and severity of venous abnormalities, and in the clinic population, make reliable correlation of duplex findings with clinical state very difficult. There is also unlikely to be a single causative abnormality leading to the development of varicosities; more likely, there is a combination of environmental and genetic factors.
