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Genetic Cause For Varicose Veins

Many patients ask their provider this question, “why did I get these horrid varicose veins?”
That is often followed by a clarification phrase. “I know my father (mother etc) had them, but why me?”

The answer may be an inherited FOX C2 gene mutation (Full name Fork Head gene domain).
It promotes and manages terminal rather than segmental development. It is also known as the “winged helix.”

There are 50 FOX genes within the human genome. Fox A-P with 1-4 subclasses etc. More may be discovered.

Unfolded the gene mutation location on the 16th chromosome is marked by the red line, q24.18.

That red line is very likely to be the root cause of your varicose veins!

This common gene mutation (25%-30% of the adult population have it, fortunately, it does not affect your mental ability!) is located on the 16th chromosome that is one of the 46 paired chromosomes that are necessary for creation of genetically normal human beings. One set (23) from your mother and the other set (23) from your father and they pair up to make you.

The mutation exists on the 24th position on that 16th chromosome and right at that position is a set of important and detailed instructions for transfer RN’ase to lay down a micro-filamentous protein called ACTIN. Actin is one of the three components of the cytoskeleton, (the other two are: intermediate filaments and microtubules). Micro-filamentous actin provides a skeleton for non-bony structures. It comes as G actin (globular) and F actin (filamentous). Such scaffolding permits rapid remodeling in response to its environment and internal signals. With the Fox C2 mutation that adaptive capacity is weakened. The discovery of actin is credited to Bruno Ferenc Straub in 1942 then a young biochemist working at the time in Albert Szent-Gyorgyi’s laboratory at the Institute of Medical Chemistry at the University of Szeged, Hungary – both became Nobel Prize winners for their discoveries. Their work only became known in the west in 1945 after World War II had ended. Like DNA actin has a double helix structure with a spiral of exactly 166° to correctly orientate. The helix repeats every 37nm. F actin appears to be a string accumulation of G actin molecules. Each molecule of F actin is bound to a molecule of ATP or ADP and is associated with a Mg2+ cation.

F ACTIN (double helix)

Filamentous actin is critical for the formation, durability and hemodynamic strength of venous valves and vein walls and in people with this chromosome mutation the transfer RN’ase instructions set is incorrect and a weak actin is laid down (it likely has poor hydrogen bonds, it may also be depleted of Mg2+ and or ATP or ADP) and over time with this weak adaptive mutation, venous valves will fail and varicose veins will begin to appear usually from puberty and onwards. Once varicose veins are clinically apparent they will steadily deteriorate. Symptoms including: pain, swelling, heaviness, leg discoloration, skin staining, skin breakdown etc, will appear. Some symptoms may be improved with compression hose, but compression hose alone will never cure varicose veins. Resolution will likely require intervention.

All that is necessary for the development of varicose veins is inherited weak F actin.

Once that is present then there are many precipitating factors that will promote the clinical appearance of varicose veins: Overweight, puberty, pregnancy, female gender, smoking, maybe prolonged standing, but not crossing legs etc.

Now there are 46 chromosomes that make up genetically normal human beings and on each chromosome are about 900 genes – and here’s the kicker – each gene has about 90 million base pairs! There are only four different types of base pairs: There are only two kinds of bases complimenting the pairs they are either purines or pyrimidines. The two sets of base pairs in DNA are guanine which compliments cytosine and the other pair is adenine which compliments thymine. (Scientists Watson and Crick figured this out (the DNA double helix) in the summer of 1952 and were awarded the Nobel Prize in medicine in 1962 for their brilliant discoveries). Chargaff’s Rule mandates that the fraction of one base strand MUST equal its compliment of the complimentary strand of DNA or RNA. What this means if a geneticist is given a strand of DNA with 35% guanine if his/her task is to make another complimentary strand of DNA/RNA it MUST contain 35% cytosine. The distance between the two stands is very precise – it has to be 10.85 Angstroms (that is controlled by many very strong hydrogen and phosphate bonds linking both strands) and the angle connecting each base pair must be 51.5°. That is the expected conformation of the double helix spiral of both DNA and RNA. Obviously when viewed from above the circular diameter of the double helix will be 10.85 Angstroms. (One Angstrom is 1 ten-billionth of a meter, to give you some idea of the scale of the double helix of DNA/RNA).

A DNA base pair string looks like this: (Note these strings are normally 90,000,000 long to make up one gene!


Whereas a typical RNA base pair string looks like this:


You may notice thymine is replaced by uracil in RNA.

DNA replication

It may be possible in the future using the Human Genome Project 1990 (Craig Venter Celera Genomics [privately funded $300,000,000] got there first, the publically funded NIH project cost $3 billion and didn’t really get there) or some as yet un-invented genetic tool to actually be able to sort out the precise base pair abnormality(ies) causing the Fox C2 gene mutation. Venter/Celera applied for a patent on some 200-300 genes Celera had mapped. President Clinton in March 2000 announced that the genome sequence could not be patented and the biotech market segment (Celera in particular) lost about $50 billion market capitalization in 48 hours. (Never ever underestimate government interference in private markets and health care in general). There are about 50 billion base pairs within the human genome.

So far we have gotten to the 16th gene on its 24th position but we have 900 x 90,000,000 details to sort out and find out where and how the base pair(s) mutation is occurring. The mutation might be only two to four base pairs for all we know or it could be hundreds or thousands long. That’s a rather onerous task! Once (if) that is done, however, it is feasible to think that we might then be able to construct a helical DNA base pair repair in the lab, splice the correction into a segment of appropriate DNA strand, attach that repaired DNA to a vector such as an adenovirus, turn that into a nasal spray and have patients detected with the gene mutation (by family genetic history) and then have the patient (I suspect that will need to be at or near birth) and spray the base pair correction(s) up an infant’s nose, which should go to the 24th position on the 16th chromosome. Genetic engineering (in humans) brings in complicated ethical issues. What if something goes terribly wrong?

Such a DNA splice could theoretically result in a genetic cure for varicose veins! If that occurred and was widespread then Optima Vein Care would go out of business. But for the foreseeable future that is not in the cards.

The FoxC2 gene mutation is found in many cases of Lymphedema Distichiasis (LD) and is a common finding in Varicose Veins. Unfortunately there is also a link to hemorrhoids.

This gene mutation was detected and analyzed in 2005 in 2,060 matched female twins; there were two types of twins: dizygotic and monozygotic. The familial concordance rates with the FOX C2 gene mutation were: 72% varicose veins and 64% hemorrhoids. The confidence interval on these findings was 95% reliable range 73% to 99%). Concordance rates were higher for dizygotic twins. Variable penetration might explain the lack of a 100% concordance.

Conclusion: the FOX C2 gene is important in the development in familial varicose veins.


The Fox C2 gene is an autosomal dominant gene (not a recessive gene) and it is not sex-linked
That means both males and females may both carry the gene, but it is variably penetrant. What that means is that the gene when fully penetrated will likely express varicose veins on both legs and may involve both the great saphenous and the short saphenous veins. As the level of penetration in the zygote declines, one leg may be affected while the other leg remains event-free (but the future may disclose increasing involvement of the other leg), still less penetration may result in reticular veins (larger veins visible under the skin but not varicosed – they have the potential to deteriorate), and still less penetration may result in ugly spider veins. Also the variable penetration may well account for why one sibling and not another will get the condition. The variable penetration also explains why one family generation may skip the condition but the next generation may get it. However, all members of the family gene pool will be carriers of the Fox C2 F actin mutation. That means that subsequent generations will develop varicose veins with a high level of predictability.

At this time we cannot switch off this gene or repair it therefore additional sets of varicose veins may appear and need additional therapy.

John C Opie MD, FRCS, FRSC(C)


Linkage to the Fox C2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs.
Ng MY, Andrew T, Spector TD et al. Lymphedema Consortium. Twin research and Genetic epidemiology Unit St Thomas’ Hospital, London ,SE17EH. J Med Genet 2005 Mar: 42:235-9