Vitamin K: CYP4F2 and VKORC1 Genetic Variants

Vitamin K is one of those vitamins that doesn’t get a lot of press. You may have heard of it in relation to preventing osteoporosis, but it turns out this little-known vitamin impacts overall health as we age.

Vitamin K Genes: Bleeding and Bones

There are two different forms of Vitamin K:

  • Vitamin K1, a fat-soluble vitamin needed by our bodies, synthesizes the proteins responsible for blood coagulation.  Without vitamin K1, also known as phylloquinone, bleeding is hard to control.
  • Vitamin K2, also known as menaquinone, comes in several different forms (MK-4, MK-7, MK-8, MK-10). It helps maintain bone strength.  Additionally, higher levels of K2 have shown to reduce calcification in the arteries[ref], as well as possibly playing a role in mitochondrial function.[ref]

Vitamin K levels have links to osteoporosis (low bone density). Lower vitamin K levels are associated with a higher risk of osteoporosis.[ref]

Beyond coagulation and bone health:

Recent studies show vitamin K plays an important role in preventing several age-related diseases.

Vitamin K interacts with vitamin D and calcium. It is important in the interplay between calcification and inflammation.

Vitamin K is also an important co-factor for reactions involving the enzyme vitamin K carboxylase. These enzyme-catalyzed reactions activate VKD (vitamin-K dependent) proteins.[ref] While the most well-known VKD proteins are involved in blood clotting, recent research has shed a lot of light on VDK proteins that contribute to vascular calcification as well as apoptosis.[ref]

The role of K2 in mitochondrial function is still being determined, but more recent research shows some promising results. It acts as an intercellular antioxidant, and it also acts as an electron carrier in the mitochondria.[ref][ref]

Where do we get vitamin K from?

We get vitamin K1 from eating green plants, as phylloquinone is a part of the photosynthesis process.

Pasture-raised eggs, dairy, and organ meat as well as fermented soy (natto) contain the highest amounts of vitaminK2. We can also convert K1 toK2 in some organs of our bodies, and certain residents of our gut microbiome (E. coli especially) convert K1 to K2 for us.


Genetic Variants that Impact Vitamin K Metabolism:

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CYP4F2 gene:

The CYP4F2 codes for the enzyme involved in converting both vitaminK1 and vitaminK2 (MK-4) to oxidized forms, thus regulating the amount of vitamin K available.[ref]

Genetic variation in the CYP4F2 gene causes people to naturally have higher or lower levels of vitamin K available, which can affect blood clotting. Warfarin, a commonly prescribed blood thinner, works by acting on vitamin K, and CYP4F2 variants can affect Warfarin dosage levels.

A quick note of caution on Warfarin dosages: While the information provided here is based on research studies, you should always talk with your doctor about questions on medications. There are multiple genetic variants affecting the metabolism of a drug.

Because the body regulates the amount of vitamin K via CYP4F2, someone with a genetic variant that slows down their CYP4F2 production could have higher circulating levels of vitamin K, depending on the foods that they have eaten.[ref] Thus Warfarin dosages may need to be higher for someone with an impaired CYP4F2. (If you are wondering why so many studies on Warfarin exist…about 30 million people in the US prescribed the drug each year.[ref])

CYP4F2 also helps in the breakdown of certain omega 6 fatty acids as well as vitamin E, so it plays an important role in our body’s inflammatory response.

Check your genetic data for rs2108622 (23andMe v4, v5 ; AncestryDNA):

  • T/T: reduced CYP4F2 function, possibly need higher Warfarin dosages[ref][ref][ref], somewhat increased risk of stroke[ref][ref] CYP4F2*3
  • C/T: reduced CYP4F2 function, possibly need higher Warfarin dosages[ref][ref], somewhat increased risk of stroke[ref][ref]
  • C/C: typical

Members: Your genotype for rs2108622 is .

Check your genetic data for rs1558139 (23andMe v4; AncestryDNA):

    • A/A: lower risk of stroke[ref] possibly increase CYP4F2 function
    • A/G: slightly lower risk of stroke
  • G/G: typical

Members: Your genotype for rs1558139 is .

VKORC1 Gene:

VKORC1 is the gene that codes for vitamin K epoxide reductase complex subunit 1. Basically, VKORC1 is responsible for recycling vitamin K back to the active form, which is then involved in activating clotting factors.[ref][ref]

The anticoagulant Warfarin acts on VKORC1, preventing it from activating clotting proteins. Variants in VKORC1 then can play a big role in the amount of Warfarin that is needed.

Check your genetic data for rs9923231 1639G/A (23andMe v4, v5):

  • C/C: typical VKORC1 activity, increased risk of lupus (Asian population)[ref]
  • C/T: decreased VKORC1 activity, increased Warfarin sensitivity (lower dose)[ref], increased stroke risk[ref]
  • T/T: decreased VKORC1 activity, increased Warfarin sensitivity (lower dose)[ref], increased stroke risk[ref]

Members: Your genotype for rs9923231 is .

 

Check your genetic data for rs9934438  1173C>T(23andMe v4, v5):

  • G/G: typical VKORC1 activity,
  • A/G: decreased VKORC1 activity, increased Warfarin sensitivity (lower dose)[ref], somewhat increased risk of aortic calcification[ref]
  • A/A: decreased VKORC1 activity, increased Warfarin sensitivity (lower dose)[ref], increased risk of aortic calcification[ref]

Members: Your genotype for rs9923231 is .


Lifehacks:

Dietary Sources:

Vitamin K is a fat-soluble vitamin, and including fat while eating green veggies will increase your absorption. Most animal sources of vitamin K2 are naturally found with fat.

Conversion of vitamin K2 in the gut microbiome is dependent on having a good gut microbiome — so if you have been on a broad-spectrum antibiotic recently, your vitamin K conversion may be impaired.

Vitamin K Supplements:

If you aren’t getting enough vitamin K through food sources — specifically enough vitaminK2 through pastured eggs and dairy or from natto — you may want to look into a vitamin K supplement.

MK4, a type of vitamin K2: Osteoporosis studies have shown that doses of 45mg/day of MK-4 were effective in preventing bone loss in postmenopausal women.[ref] This is a really high dose of vitamin K, but there have been multiple studies using this dose of MK-4 (mostly in Japanese women).[ref]

While there is no known upper limit or toxicity set for vitamin K1 or K2  supplementation, there are user reviews showing that a few people react poorly to too much MK-7. So just a word of warning to pay attention to how you feel if you start taking higher doses of MK-7.

Interaction with Warfarin: Resveratrol, in high doses, may increase Warfarin’s anticoagulation activity. This was a mouse study, though, so it may not hold true for humans.[ref]

More to read: Chris Masterjohn’s Ultimate Vitamin K2 Resource has a lot of good information about vitamin K supplements.

 

Warfarin Dosage Calculator:
If you are comfortable with uploading your genome to Stanford, there is a nifty little calculator that gives an estimate (for informational purposes only) of warfarin dosage.


Related Articles and Genes:

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Ancestral Diet: Omega-3 and Omega-6 Fatty Acids Impact the FADS1 gene
At one point, researchers thought that butter will give you a heart attack. Therefore, we should only cook with Crisco, vegetable oil, canola oil, olive oil. Wait — everyone is switching back to butter now… while eating flax seeds for their omega-3s.

 

 

Originally published: June 2018. Revised and updated: Jan. 2021



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.