Lymphedema: Causes and Genetic Pathways

Key takeaways:
~ Lymphedema is caused by interstitial fluid building up under your skin, often in the legs or arms.
~ Impairments to the lymphatic vessels prevent the fluid from moving out of the tissue.
~ Genetic variants can increase the risk of lymphedema, pointing you towards the underlying cause as well as targeted solutions.

Members will see their genotype report below, plus additional solutions in the Lifehacks section. Consider joining today

What is lymphedema?

Lymphedema occurs when interstitial fluid builds up under your skin—for example, noticeable swelling in one leg. Lymphedema affects about 3 million people in the US and 200 million worldwide.[ref]

Lymphedema can be mild, with minor swelling and minor discomfort. Or, it can be more severe, causing a lot of swelling and pain.

The buildup of interstitial fluid is due to impaired lymphatic vasculature. Lymph moves through lymph vessels, and lymphedema occurs when the lymphatic system can’t filter and drain fluid out of areas downstream of the disrupted or impaired areas. Over time, this accumulation of fluid can cause swelling, discomfort, and even infections.

Recent research has shed light on the role of genetics in lymphedema. Studies have identified several genetic variants that can increase an individual’s risk of developing this condition. By understanding these genetic factors, you and your healthcare provider may be able to target the most effective solutions tailored  for you.

Types of Lymphedema: Hereditary and Secondary

Primary lymphedema is caused by rare genetic mutations. It can start in infancy (Milroy’s disease), in the teen to young adult years (called Meige’s disease), or in middle age or beyond (lymphedema tarda).

Secondary lymphedema is the disruption of lymph drainage. It is most often caused by trauma or cancer treatment that damages a lymph node. Venous insufficiency or kidney disease can also be a cause of secondary lymphedema. In some regions of the world, exposure to a nematode parasite can cause lymphedema. This is the most common type of lymphedema.

Quick note – not all edema (fluid) is lymphedema. There can also be swelling and fluid retention problems with your veins.

What is going on in lymphedema?

Before we get into the details, let’s briefly tour the lymphatic system.

The lymphatic system moves a fluid called lymph throughout the body. Like the circulatory system for blood, the lymphatic system moves fluid from tissues back into central circulation.

Lymph fluid originates in interstitial fluid – the fluid between cells. The lymph fluid is similar to blood plasma. It moves into small lymph capillaries and then into larger vessels and through the lymph nodes.

In the lymph nodes, lymphocytes (a type of white blood cell) filter out any foreign particles — viruses, bacteria, and cancer cells.

Another job the lymphatic system does is to transport fats absorbed in the digestive system.[ref]

Circling back to lymph forming from interstitial fluid… This fluid comes from the circulatory system. At the end of the capillaries that bring in blood from the heart is an area where the lymph fluid is formed. Most of the blood in this area will return to the heart in the venous capillaries, but about 10% of the fluid will enter the lymphatic system.


From PMC6459625 – excellent overview of the lymphatic system.

There is no pump for the lymphatic system like the heart pumps blood in the circulatory system. In the lymphatic system, the flow is slow due to peristalsis, various lymph valves, and the movement of adjacent muscles.

If excess pressure develops within the lymph system, fluid can leak back into the interstitial space. This causes the ‘swelling’ seen in lymphedema. 

When the fluid accumulates, it can impact cell behavior within that specific tissue. One thing that can happen is that immune cells can be activated in the area, or fibrosis can occur.[ref]

Diagram of lymphatic vessels from PMC6434710 – open article, in-depth information on lymphedema

Secondary Lymphedema: Diving Deeper

Secondary lymphedema is the most common type of lymphedema. It is caused by disruption or obstruction in the lymph vessels, resulting in the build-up of interstitial fluid.

For example, arm and chest lymphedema are a common problem for women who have had breast cancer treatment that damages the lymphatic vessels. A recent study on breast cancer survivors with lymphedema found that inflammatory biomarkers were elevated for several months after surgery.

Interestingly, women with lymphedema after cancer treatment were more likely to have had higher baseline (pre-surgery) levels of inflammatory biomarkers such as IL1A and IL6. Additionally, higher pre-surgery VEGF (Vascular Endothelial Growth Factor) levels were also linked to an increased susceptibility to secondary lymphedema.[ref]

Another common cause of lymphedema is the infiltration of the lymphatic vessels by a parasite called Wuchereria bancrofti. This is mainly a problem in tropical developing countries or for people who have traveled to those areas.

So… what initiates the lymphedema?

Leukotrienes: Inflammatory mediators driving lymphedema

Leukotrienes are inflammatory mediators derived from lipids. For example, immune system cells, such as neutrophils, macrophages, and mast cells, can form leukotrienes from arachidonic acid (omega-6 fat).

LTB4 (leukotreine B4) is a leukotriene that is involved in lymphedema. LTB4 is produced in response to inflammatory cytokines, increasing leukocytes’ ability (white blood cells) to cross through the endothelium (cells lining blood vessels and lymph vessels).

Animal studies show that LTB4 plays a central role in secondary lymphedema. Leukotrienes are produced in response to inflammation, thus making tissue inflammation central to the development of lymphedema.[ref]

Leukotriene B4 (LTB4) is an inflammatory lipid mediator synthesized from arachidonic acid using the enzyme 5-LO (ALOX5 gene, below in the genotype section). The final step in the production of LTB4 involves the LTAH4 enzyme (also below).

Once synthesized, LTB4 can increase vascular permeability. This is important during active infection for immune system cells to respond to the site of the inflammation. However, vascular permeability after the infection needs to be halted.

LTB4 binds mainly to the BLT1 receptor. Neutrophils (a type of white blood cell) react by increasing the inflammatory response.

The increased inflammatory response initiated by leukotriene B4 interacts with lymphedema in a couple of ways.

FOXC2 (in the genotype report) is essential for maintaining the integrity of the lymphatic system, especially in the areas around the lymphatic valves that keep lymph flowing in the right direction. FOXC2 also interacts with activated T cells in inflammation.[ref]

Increased fluid accumulation along with the leukotriene B4 molecule activates more of an inflammatory response to the area. It builds on itself. As the lymphedema persists for a longer time, the pro-inflammatory cytokines can cause fibrosis – thickening or scarring – in the area.[ref]

Genetic Polymorphisms and Lymphedema:

Lymphedema due to physically damaged lymph vessels can happen to anyone, especially after surgery or cancer treatment.[ref] However, some people are more susceptible to secondary lymphedema than others. The genetic variants listed below in the genotype report are linked to leukotriene B4 formation, inflammatory cytokines, and lymphatic system development.

Lymphedema Genotype Report:

ALOX5 gene: catalyzes the first step in synthesizing leukotriene. Also important in the creation of pro-resolving mediators for the resolution of inflammation.

Check your genetic data for rs4987105 (23 and Me v4; AncestryDNA):

  • C/C: most common genotype (higher levels of type 2 diabetes, higher levels of C-reactive protein – a study done in the EU)[ref]
  • C/T: decreased risk of type 2 diabetes, lower levels of inflammation, and possibly lower lymphedema
  • T/T: decreased risk of type 2 diabetes, lower levels of inflammation, and possibly lower lymphedema[ref]

Members: Your genotype for rs4987105 is .


LTA4H gene: catalyzes the final step in the biosynthesis of leukotriene B4

Check your genetic data for rs1978331 (23andMe v4, v5; AncestryDNA):

  • G/G: lower levels of LTA4H, which catalyzes the final step in the synthesis of leukotriene B4 [ref][ref]
  • A/G: lower levels of LTA4H, which catalyzes the final step in the synthesis of leukotriene B4
  • A/A: typical

Members: Your genotype for rs1978331 is .

MMP2 gene: encodes a metalloproteinase important in tissue repair, inflammation, and new blood vessel formation

Check your genetic data for rs1030868 (23andMe v4):

  • G/G: typical
  • A/G: higher risk of secondary lymphoma
  • A/A: higher risk of secondary lymphoma[ref]

Members: Your genotype for rs1030868 is .

Check your genetic data for rs2241145 (23andMe v4):

  • G/G: typical
  • C/G: higher risk of secondary lymphoma
  • C/C: higher risk of secondary lymphoma[ref]

Members: Your genotype for rs2241145 is .

FOXC2 gene: encodes a transcription factor involved in tissue formation for lymphatic vessels and the inflammatory response in lymphatic tissue

Check your genetic data for rs34221221 (23andMe v4; AncestryDNA):

  • C/C: increased gene expression (likely higher risk of secondary lymphedema)[ref]
  • C/T: increased gene expression (likely higher risk of secondary lymphedema)
  • T/T: typical

Members: Your genotype for rs34221221 is .

TNF gene: encode TNF-alpha, an inflammatory cytokine

Check your genetic data for rs1800629 -308A/G (23 and Me v4, v5; AncestryDNA):

  • A/A: higher TNF-alpha levels; increased risk of complications with lymphedema[ref]
  • A/G: somewhat higher TNF-alpha levels
  • G/G: typical

Members: Your genotype for rs1800629 is .

TLR4 gene: encodes toll-like receptor 4, a key immune system receptor that is expressed on B cells, macrophages, and mast cells

Check your genetic data for rs4986791 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased risk of complications with lymphedema
  • T/T: increased risk of complications with lymphedema[ref]

Members: Your genotype for rs4986791 is .

VEGFR3 gene: receptor for vascular endothelial growth factor, which is important in vessel growth

Check your genetic data for rs10464063 (AncestryDNA):

  • C/C: typical
  • C/T: typical
  • T/T: increased risk of secondary lymphedema (study of cancer patients)[ref]

Members: Your genotype for rs10464063 is .

Lifehacks: 10 Natural solutions for lymphedema

Talk with your doctor about your options for lymphedema. Common treatments include compression garments and manual lymph drainage.

Research shows that the accumulated fluid in lymphedema exacerbates the problems and causes more immune cells to infiltrate the tissue. Early intervention may be key, so don’t put off talking to your doctor about your options.[ref]

1. Physical therapy plus manual lymphatic drainage therapy:

Clinical trials show that both physical therapy and manual lymphatic drainage are beneficial in reducing lymphedema in cancer patients.[ref]

2. Aquatic Training:

A study found that moderate-intensity aquatic training exercises (water bikes, aqua-jogging, trampoline) for six weeks significantly decreased limb circumference and decreased lymphatic fluid.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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