Understanding Vein Disease

Is It in Your Genes? The Genetics of Varicose Veins

By Dr Johan Blignaut, Specialist Surgeon · Vein Centres South Africa · October 2026

“My mother had them, and my grandmother had them. Was I always going to get them?” I hear some version of this question in the consulting room almost every day.

It is a good question. Family history is one of the strongest clues we have to who develops varicose veins, and over the past decade genetic research has moved from simply saying “it runs in families” to identifying specific genes and biological pathways involved.

This article explains what that research has found, which genes scientists are paying most attention to, what genetics can and cannot tell you today, and why none of it changes the most important step in your care: finding out which vein is actually causing the problem.

The short answer

Yes, varicose veins have a real genetic component — but there is no single “varicose vein gene”. Susceptibility is polygenic: well over a hundred locations in the human genome each influence risk by a small amount.^5,7

The genes identified so far cluster around a handful of biological themes:

• how the lining of the vein senses and responds to blood flow
• how venous valves form and are maintained
• the strength and structure of the vein wall, including collagen, elastic fibres and their supporting proteins
• inflammation and vascular signalling
• body size, particularly height

Inheriting a higher genetic risk does not mean you will definitely develop varicose veins. It means your veins may be more susceptible to the other forces — age, pregnancy, body weight and prolonged standing — that act on them over a lifetime.

How strongly do varicose veins run in families?

The most quoted figures come from a 1994 French study that examined 134 families — 67 people with varicose veins aged 30 to 40, 67 without, and all of their parents.¹

These numbers are striking, but they come from a small study and are often repeated online without that caveat. They demonstrate a strong familial pattern; they are not a precise prediction for an individual patient.

A larger German study recruited 2,701 patients with chronic venous disease and collected information about their first-degree relatives, generating 4,033 nuclear families comprising more than 16,000 individuals.²

The estimated narrow-sense heritability was about 17% for chronic venous disease overall and 18.5% for uncomplicated varicose veins. In other words, inherited genetic differences explain a meaningful — but far from complete — part of the variation in susceptibility across a population. They do not give an individual patient a 17% “genetic risk”.

From families to genomes: what the large studies have found

Family studies tell us that genes matter. To find which genes, researchers use genome-wide association studies (GWAS). These studies compare the DNA of hundreds of thousands of people with and without varicose veins, looking for small genetic variations that are more common in one group than the other.

The arrival of very large biobanks — including the UK Biobank, Finland’s FinnGen and the US Million Veteran Program — transformed the field.

More recently, researchers have moved from GWAS to sequencing the protein-coding parts of the genome, known as exome sequencing. This can identify rarer variants that may have larger biological effects.

A 2024 analysis of more than 350,000 UK Biobank exomes strengthened the evidence for PIEZO1 and identified rare-variant associations involving ECE1 and FBLN7, although the latter two signals were less robust in sensitivity analyses.⁸

A 2026 systematic review identified 13 genome-wide studies involving more than 600,000 people with varicose veins. Across them, implicated genes clustered particularly around inflammation and immunity, blood-pressure regulation and vascular architecture — but many associations have not yet replicated consistently across different populations.¹⁸

A useful sign that some of these findings are genuine is that the same genes and pathways keep appearing across independent studies, populations and research methods.

The genes researchers are watching most closely

Of the many genes now linked to varicose veins, a few stand out because they appear repeatedly and make biological sense.

PIEZO1 — the vein’s pressure and flow sensor

PIEZO1 is currently one of the most consistently implicated genes.^3,5,8

It makes a mechanically activated ion channel in cells lining blood vessels. The channel opens when the cell is stretched or when blood flow exerts mechanical force across it. In effect, it allows the vessel wall to “feel” changes in flow and pressure.

The discovery of the PIEZO channels contributed to the 2021 Nobel Prize in Physiology or Medicine.

Several lines of evidence point towards a role in venous disease:

• In families and populations: rare variants that disable one copy of PIEZO1 have been associated with varicose veins and with a greater likelihood of having undergone vein ablation.⁹
• In valve development: mice lacking endothelial PIEZO1 failed to form iliac venous valves normally, providing experimental evidence that this flow sensor participates in venous-valve development.¹⁰
• In diseased veins: studies of varicose tissue have found abnormalities in PIEZO1-related signalling.^11,12

It is an attractive biological explanation. If a vein cannot properly sense the forces generated by blood flow and pressure, it may remodel abnormally, and the development or maintenance of venous valves may also be affected.

However, as discussed later, scientists do not yet agree on whether PIEZO1 activity is too low or too high in established varicose veins.

CASZ1 — the strongest common signal

In the first large UK Biobank study, the single strongest genetic association was in CASZ1, a gene involved in blood-vessel development and also linked to blood pressure.³

It has been replicated in several populations.

Exactly how it influences venous disease remains uncertain. Rare damaging variants in CASZ1 have not shown the same pattern seen with PIEZO1.⁹

Valve-development genes

Venous valves are formed during development through a highly regulated genetic programme.

Genes involved in this process include FOXC2, GJC2 and GATA2, together with members of the calcineurin–NFAT pathway such as PPP3R1 and NFATC2.^4,5,14

Importantly, some of these genes appear both in rare inherited valve disorders and in large population genetic studies.

This overlap strengthens the evidence that inherited differences in venous-valve development and maintenance contribute to susceptibility.

Vein-wall structure genes

Varicose-vein walls show abnormalities in collagen, elastic fibres and the extracellular matrix that supports the vessel wall.

Fittingly, several identified genes code for structural proteins or regulators of this matrix, including COL27A1, EFEMP1, FBLN7, MFAP2 and TGFB2.^5–8

These findings support the idea that varicose veins are not simply a problem of valves. The vein wall itself is biologically different.

Overlap with blood clots

The 2023 multi-ancestry study found that factor V Leiden, the well-known inherited thrombophilia caused by a variant in F5, is also associated with varicose-vein risk.⁷

Genetic susceptibility to varicose veins also overlaps with susceptibility to venous thrombosis, peripheral arterial disease and abdominal aortic aneurysm.⁷

A Swedish nationwide family study had already shown that varicose veins and venous thromboembolism share familial susceptibility.¹⁹

This does not mean that having varicose veins automatically implies a clotting disorder. It does mean that the biological overlap between venous disease and thrombosis is more complex than previously appreciated.

Protective variants

Not every genetic discovery increases risk.

A low-frequency variant in GJD3, which codes for a gap-junction protein involved in communication between cells, is associated with a lower risk of varicose veins.⁶

The variant is much more common in Finland than elsewhere in Europe.

Protective variants are especially interesting to researchers because they can reveal what happens when a biological pathway is naturally turned down.

Other genes under investigation

HFE, best known as the major gene associated with hereditary haemochromatosis, has also appeared in genetic studies of venous disease.⁴

Older clinical work suggested that the C282Y variant may influence susceptibility to venous leg ulceration in patients who already have severe chronic venous disease.¹⁷ This association has not become part of routine venous assessment.

At a glance

When a single gene does matter: rare inherited conditions

Ordinary varicose veins are polygenic.

A small number of uncommon conditions are different: a change in one gene can have a large effect, and the venous problem is usually part of a broader syndrome.

Lymphoedema–distichiasis — FOXC2

People with lymphoedema–distichiasis develop swelling due to abnormal lymphatic vessels and often have an extra row of eyelashes.

Venous reflux is strikingly common. Imaging studies have shown substantially fewer venous valves, with remaining valve leaflets significantly shorter than normal.^13,14

Other primary lymphoedemas — GJC2

Mutations in GJC2, another gap-junction gene, can also affect venous-valve number and morphology.¹⁴

Venous valve aplasia — EPHB4

Rare variants in EPHB4 have been associated with families in whom venous valves are markedly reduced or almost absent.¹⁵

Klippel–Trénaunay syndrome — PIK3CA

Klippel–Trénaunay syndrome combines vascular malformations, abnormal superficial veins and overgrowth of part of a limb.

It is usually caused by a PIK3CA mutation that develops in only some cells after conception. It is therefore genetic, but usually not inherited.¹⁶

These disorders are rare.

They are important because they demonstrate, in an extreme form, many of the same mechanisms — valve formation, vessel growth and vascular signalling — that population studies implicate in ordinary varicose veins.

What genetics does — and does not — explain

Genetic susceptibility sets the background; what happens over a lifetime determines how much of that susceptibility becomes clinically visible.

Even very large genetic studies explain only part of inherited susceptibility.

In the 2022 UK Biobank and 23andMe study, estimated SNP heritability was approximately 5–8%, depending on the analytical method used.⁵

That remains lower than the approximately 17–18% estimated from family data.²

Rarer genetic variants, gene–gene interactions, gene–environment interactions and differences in how venous disease is measured probably account for part of the gap.

Genetics has also helped researchers test whether some associated characteristics are likely to be causal rather than simply correlated with disease.

Using Mendelian randomisation, large studies have supported a causal contribution from greater height and higher body-mass index to varicose-vein susceptibility.^3,5

Pregnancy and previous deep vein thrombosis remain important clinical risk factors, although their biological relationship with venous disease is more complex.

What genetics does not tell us is equally important.

It cannot currently tell an individual patient:

• where venous reflux starts
• which vein is incompetent
• how extensive the reflux is
• whether symptoms are actually caused by the visible veins
• which treatment, if any, is appropriate

Two sisters may share much of their genetic background and still show completely different patterns of reflux on duplex ultrasound.

A gap that matters in South Africa

The genetic evidence base remains overwhelmingly weighted towards populations of European ancestry.

In the 2026 systematic review, 12 of the 13 included genome-wide studies relied predominantly on European cohorts; one used Taiwan Biobank.¹⁸

There is still no comparable large genomic study of varicose veins in a South African population.

The 2023 Million Veteran Program study was an important step forward because it combined data from people of European, African, Hispanic and East Asian ancestry.⁷ Including multiple ancestries also helped researchers narrow down likely causal variants more precisely.

However, African-ancestry participants were largely drawn from populations outside Africa, and the combined dataset remained heavily weighted towards European ancestry.

African populations contain more human genetic diversity than populations from any other continent. Risk variants that are common in Europe may be uncommon in Southern Africa, while variants that matter here may not yet have been discovered.

For a genetically diverse country such as South Africa, the genetic picture described in this article should therefore be viewed as a starting point rather than a complete map.

Should you have a genetic test for varicose veins?

For ordinary varicose veins, no.

There is currently no validated clinical genetic test that can reliably predict whether you will develop ordinary varicose veins or guide how they should be treated.

Researchers can calculate a polygenic risk score, combining information from many risk variants.

In the 810,625-person study, people with higher polygenic risk were more likely to have varicose veins and to have undergone varicose-vein surgery.⁵

That is scientifically interesting, but these scores:

• explain only part of the inherited risk
• have been developed mainly in populations of European ancestry
• do not identify where venous reflux occurs
• do not currently alter treatment decisions

For that reason they are not part of routine clinical practice.

A consumer DNA kit is therefore unlikely to tell you anything clinically useful about ordinary varicose veins that your family history, examination and duplex ultrasound cannot already tell us more directly.

Your family history remains the most practical genetic information you can provide — so tell your doctor about it.

The exception is when venous disease occurs as part of one of the rare inherited syndromes described above. In those circumstances, assessment by a clinical geneticist may be appropriate.

Could genetics lead to new treatments?

That is one of the main reasons this research matters.

At present, effective treatment for established venous reflux remains physical: compression can reduce symptoms, while sclerotherapy or endovenous treatment can close incompetent veins.

No tablet can currently restore an incompetent venous valve to normal.

Genetic research offers a potential route towards future medical therapies because it identifies specific biological pathways and potential drug targets.

Across drug development, targets supported by human genetic evidence have historically had a higher probability of success, in some analyses more than two-fold when the causal gene is relatively clear.²⁰

Large varicose-vein studies have highlighted genes and pathways that may eventually become therapeutically relevant, including VEGFA, EFEMP1, PPP3R1 and NFATC2.^5,7

The PIEZO1 puzzle

PIEZO1 illustrates how much there is still to learn.

Recent research appears to point in two different directions.

• In one experimental study, PIEZO1 expression was increased in human varicose-vein tissue, while deleting endothelial Piezo1 in mice reduced experimentally induced venous dilatation, inflammation and vascular leakiness.¹¹
• In another study of human veins and endothelial cells exposed to abnormal flow, PIEZO1 signalling was reduced. Experimentally activating PIEZO1 restored protective signalling pathways in the laboratory.¹²
• In population studies, rare variants that reduce PIEZO1 function appear to increase susceptibility to varicose veins, while other genetic findings suggest that greater activity may in some circumstances be protective.^8,9

One possible explanation is that PIEZO1 needs to operate at the right level, in the right cell, at the right stage of disease.

Too little signalling may impair normal adaptation to blood flow or valve development, while excessive or abnormal signalling in established disease may promote inflammation or remodelling.

That remains a hypothesis rather than a proven clinical model.

None of these experimental approaches has yet been shown to treat varicose veins in patients.

For now, the main practical value of the genetics is understanding: it confirms that varicose veins are a genuine disorder involving the vein wall, valves, endothelial biology and flow-sensing mechanisms — not simply a cosmetic quirk or the result of crossing your legs.

What this means if varicose veins run in your family

You cannot change your genes.

Inherited susceptibility, however, is not the same as inevitability.

Several practical things remain worthwhile:

• Know your family history. Tell your doctor if a parent or sibling had varicose veins, venous leg ulcers or deep vein thrombosis.
• Keep the calf muscle pump working. Regular walking and avoiding prolonged immobility support venous return.
• Maintain a healthy weight. Higher body-mass index appears to contribute causally to varicose-vein susceptibility.
• Use compression when appropriate. Compression stockings can reduce symptoms in selected patients and can be useful during pregnancy or prolonged periods of standing.
• Do not ignore skin changes. Swelling, brown discolouration, eczema or hardening around the ankle can indicate more advanced venous disease and may precede venous leg ulceration.

If you do develop symptomatic varicose veins, a family history does not change the fundamental way they should be assessed.

Every patient at our centres undergoes duplex ultrasound to establish where reflux begins and how far it extends before a treatment decision is made. I explain why that matters in what actually causes varicose veins.

Treatment, when necessary, is directed at the actual source of the reflux — most commonly with endovenous radiofrequency ablation under local anaesthetic, or ultrasound-guided foam sclerotherapy.

Frequently asked questions

References

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