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Cystathionine-Beta-Synthase (CBS) is an enzyme which converts homocysteine into cystathionine, the first step of the transsulfuration pathway, and is encoded for by the CBS gene. Homocysteine is the starting molecule of the transsulfuration pathway; CBS converts homocysteine into cystathionine, which is then converted into cysteine by the action of cystathionine-gamma-ligase. This pathway provides a vital source of the amino acid cysteine, but is also the bodies only mechanism for removing sulfur containing amino acids when present in excess 1.

However, homocysteine does not just form part of the transsulfuration pathway; it also occupies a key location in the methionine and one carbon (sometimes called folate) cycles, which are together sometimes termed the methylation cycle. Methionine synthase uses 5-MTHF as a methyl donor to convert homocysteine into methionine, resulting in the reformation of THF. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme which forms 5-MTHF, and the rs1801133 (C677T) and rs1801131 (A1298C) SNPs in MTHFR are thought to lead to reduced MTHFR activity and an accumulation of homocysteine. For this reason MTHFR SNPs and CBS SNPs are often discussed together.

Regardless of which pathway homocysteine is processed through it is considered harmful when present at high levels in the blood. Excessive homocysteine can damage endothelial cells which line the circulatory system and heart, leading to inflammation and increasing the risk of coronary artery disease 2. There are numerous SNPs within CBS. Some are associated with increased cardiovascular risk, while there are several associated with gastrointestinal issues arising from issues in removing dietary sulfur. Interestingly, these SNPs divide into those which increase or decrease CBS activity, highlighting its important role in many of the bodies systems.

C1080T / A360A

Longevity
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1801181 c t 34 Ala Ala

Risk Description

The risk ‘T’ allele (in 23andme the risk allele is “A”) of rs1801181 or C1080T (also called A360A) in the CBS gene has been associated with a very mild risk of developing non-Hodgkin lymphoma 3. The risk described by the authors is mild and they are unable to describe a mechanism although an association with low dietary vitamin B6 and methionine intake was observed.

Direct Nutrients:*

Ingredient Active Ingredient Effect
Vitamin B6 Pyridoxal phosphate

Vitamin B6 is a co-factor for numerous different enzymes including CBS. The risk ‘T’ allele of C1080T was associated with an increased risk of cancer when dietary vitamin B6 was low 3, therefore carriers may benefit from supplementation.

Indirect Nutrients:*

Ingredient Active Ingredient Effect
L-Methionine

The risk ‘T’ allele of C1080T was associated with an increased risk of cancer when dietary methionine intake was low 3. It is unclear how low methionine interacts with the ‘T’ allele of C1080T.

Discuss this information with your doctor before taking any course of action.

C1039+530T

Science Grade
A-
Gastrointestinal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs4920037 c t 13

Risk Description

The risk ‘T’ allele of rs4920037 or C1039+530T in the CBS gene has been associated with an elevated risk of developmental disorders associated with a lack of maternal dietary folate or proper vitamin intake, such as cleft lip or more severe neural tube defects 46. The risk of occurrence was shown to increase with the occurrence of polymorphisms in other methylation cycle related genes such as MTHFR or BHMT.

Lifestyle Considerations:

Behavior Description
Maternal supplementation

The risk ‘T’ allele of C1039+530T is associated with development defects in conjunction with low dietary folate and vitamin intake 46.

There are no described effects in adults so dietary supplementation may only be required during pregnancy.

Discuss this information with your doctor before taking any course of action.

C699T

Science Grade
B-
Gastrointestinal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs234706 g a 28 Tyr Tyr

Risk Description

The SNP rs234706 or C699T in the CBS gene is perhaps the most widely investigated CBS SNP, and also the most controversial. Initial studies showed that the risk ‘T’ allele was associated with increased CBS activity 7, although later studies showed no risk, or even the opposite effect 8,9.

This increase in CBS activity can lead to increased production of ammonia, however the level of risk this increase imposes is unclear 10. As such and individual assessment of serum ammonia levels in association with genetic assessment is to be recommended before considering dietary alterations.

See: why CBS genes, sulfur and ammonia are on my radar

Nutritional Contraindications:*

Ingredient Active Ingredient Effect
Sulfur

The risk ‘T’ allele of C699T is associated with an accumulation of ammonia however the level of risk this accumulation induces is unclear.

Dietary adjustment is likely unnecessary unless serum ammonia levels have been found to be elevated. However, high dose sulfur supplementation (glutathione, lipoic acid) should be avoided. Some carriers may also be sensitive to epsom salt baths and high sulfur foods, such as cruciferous vegetables, eggs and garlic.

Discuss this information with your doctor before taking any course of action.

G1330A

Science Grade
B-
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs28934891 g a 0.03 Asp Asn

Risk Description

The very rare risk ‘A’ allele of rs28934891 or G1330A is associated with reduced CBS activity and an accumulation of homocysteine 11, with associated increased cardiovascular risk.

Direct Nutrients:*

Ingredient Active Ingredient Effect
Vitamin B6 Pyridoxal phosphate

It is unclear how the risk ‘A’ allele of G1330A impairs CBS function. Following vitamin B6 supplementation, a cofactor for CBS, CBS activity was restored and homocysteine accumulation was reduced 13.

Indirect Nutrients:*

Ingredient Active Ingredient Effect
Nattō Nattokinase

Nattokinase is an enzyme which is extracted and purified from a Japanese food called nattō, which is made from fermented soybeans.

Nattokinase is secreted by the bacteria involved in the fermentation process and has a very strong ability to break down fibrin blood clots 14. A beneficial effect on blood pressure, and general cardiovascular health has been described 15. Therefore, supplementation may benefit those carrying the risk ‘A’ allele of G1330A who display elevated homocysteine with an increased cardiovascular risk.

Discuss this information with your doctor before taking any course of action.

T833C

Science Grade
B+
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs5742905 t c 0.02 Ile Thr

Risk Description

The risk ‘C’ allele of rs5742905 or T833C is associated with increased levels of homocysteine in the blood and an elevated risk of cardiovascular disease 12,13.

Direct Nutrients:*

Ingredient Active Ingredient Effect
Vitamin B6 Pyridoxal phosphate

Vitamin B6 is a co-factor for numerous different enzymes including CBS. It is unclear how the ‘C’ allele of T833C leads to an accumulation of homocysteine; however an excellent response was observed following vitamin B6 supplementation 13.

Indirect Nutrients:*

Ingredient Active Ingredient Effect
Nattō Nattokinase

Nattokinase the enzyme which is purified from the Japanese food nattō, which is made from fermented soybeans.

Nattokinase has a very strong ability to break down fibrin blood clots 14 and a beneficial effect on blood pressure, and general cardiovascular health has also been described 15. Therefore, supplementation may benefit those carrying the risk ‘C’ allele of T833C who display elevated homocysteine with an increased cardiovascular risk.

Discuss this information with your doctor before taking any course of action.

T43067923C

Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs234714 c t 20

Risk Description

This variant localizes in the non-coding part of the CBS gene’s RNA and while it does not affect the amino acid make-up of the protein, it modulates its expression. The risk allele T is associated with increased homocysteine levels 16, which have been linked with increased risk of inflammation and cardiovascular disease. 

Direct Nutrients:*

Ingredient Active Ingredient Effect
SAM-e S-adenyosylmethionine

SAM-e is both a stabilizer and activator of CBS 17. Therefore SAM-e supplementation may be beneficial, although care should be taken to not oversaturate an already overloaded pathway as this may lead to further complications.

Vitamin B6

Vitamin B6 is a co-factor for numerous different enzymes including CBS 17. While T43067923C’s effects on homocysteine accumulation may result from reduced levels of CBS, supplementing Vitamin B6 will aid the efficiency of the available protein.

Iron

Iron forms the central core of the heme molecule, which is a co-factor for numerous enzymes including CBS 17. While T43067923C’s effects on homocysteine accumulation may result from reduced levels of CBS, supplementing iron will aid the efficiency of the available protein.

Discuss this information with your doctor before taking any course of action.

Dr. Aaron Gardner, BSc, MRes, PhD

Dr. Aaron Gardner, BSc, MRes, PhD is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.
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