Updated October 26th, 2017
There has been a lot of buzz about the CBS family of genes and how they impact sulfur metabolism, both from supplements like glutathione, as well as from food sources, such as cabbage, broccoli, etc. Doctors like Amy Yasko have researched a link between CBS genes and autism, but many remain skeptical. I think it’s fair to say that the science on the CBS topic is just beginning to blossom.
For my purposes, I am interested in how CBS SNPs should influence my food and supplement choices, if they should at all, and what lab tests can help confirm potential high or low CBS activity.
- What are the CBS genes and what do they do?
- The two extremes of CBS activity – down regulation and up regulation
- The SNPs associated with CBS mutations (both slow and fast) are quite common
- CBS C699T and ammonia
- My practical focus for CBS – homocysteine and ammonia awareness
What are the CBS genes and what do they do?
The CBS genes make an enzyme called cystathionine beta synthase (CBS).
CBS helps convert homocysteine into cystathionine as the first step in the transsulfuration pathway. (R) You can think of the transsulfuration pathway as the complicated chain of reactions the body undergoes to metabolize sulfur. As the chart below demonstrates, perhaps the transsulfuration pathway’s most important job is to help produce glutathione, a powerful antioxidant we need to stay in good health. (R)
Diagram by Research Gate.
Although I was taught by my law school professors to never cite Wikipedia, good information on CBS metabolism is scarce, and this Wikipedia article does a nice job of explaining its role in processing sulfur, which will be a key component of our dietary discussion below:
CBS occupies a pivotal position in mammalian sulfur metabolism at the homocysteine junction where the decision to conserve methionine or to convert it to cysteine via the transsulfuration pathway, is made. Moreover, the transsulfuration pathway is the only pathway capable of removing sulfur-containing amino acids under conditions of excess.
So, just as MTHFR genes convert homocysteine to methionine, CBS genes convert homocysteine to cystathionine. They do this as part of our body’s methylation cycle, and in the process, they rid the body of excess sulfur containing amino acids.
The two extremes of CBS activity – down regulation and up regulation
To begin, it’s important to differentiate between CBS gene up-regulation, and down regulation.
Down regulation, or diminished CBS activity, results in poor sulfur metabolism, the pooling of sulfur groups, and potentially high homocysteine.
Low CBS activity is associated with diseases like homocystinuria.
Up-regulation of the CBS genes results in rapid sulfur metabolism that can correspond with low homocysteine. We usually think of high homocysteine as the thing to avoid, but very low levels can be an issue as well. (R)
When the CBS gene is highly active, the body cycles through homocysteine at a very rapid pace. Since the body makes ammonia as a byproduct of metabolizing sulfur, some have theorized that increased CBS activity results in higher levels of ammonia, which can cause a number of health issues.
And, here’s the thing:
The SNPs associated with CBS mutations (both slow and fast) are quite common
Before we get too bogged down in the land of CBS genes, it’s important to remember that these variants are carried by a ton of people.
Here are the stats on risk allele frequency for the 4 common variants according to Livewello (T is the risk allele for all SNPs):
- rs2851391 – 40% of people have the risk allele
- rs234714 – 25% of people have the risk allele
- rs6586282 – 14% of people have the risk allele
- rs234709 – 45% of people have the risk allele
Confusing CBS SNPs – Dr. Ben Lynch emphasizes different SNPs
The SNPs listed above are referenced by LiveWello as common CBS mutations. However, Dr. Ben Lynch, a well known naturopathic doctor, and founder of StrataGene, lists different CBS SNPs as part of his program. Dr. Lynch designed StrataGene to give interpretations for the top 50 or so genes with the most clinical data.
Strategene lists these SNPs as relevant CBS mutations:
- rs234706 or C699T
- rs5742905 – CBS T8336
- rs4920037 – CBS C19150T
- rs28934891 – CBS D444N
You may notice that the focus SNPs for LiveWello don’t match the SNPs from Strategene. This discrepancy probably arises due the science being so new, with ever more studies identifying new targets. To help understand the effect these various SNPs can have on CBS function I’ve pooled the important data into the simple table below.
|SNP ID||Major/Minor (Risk)||Risk Allele Frequency||Risk Allele Effect|
|rs2851391||C/T||38%||High homocysteine/reduced CBS activity|
|rs6586282||C/T||15%||High homocysteine/reduced CBS activity|
|rs234706||G/A||28%||Reduced homocysteine/increased CBS activity|
|rs5742905||T/C||0.02%||Moderate increase in homocysteine/reduced CBS activity|
|rs4920037||C/T||13%||Reduced CBS activity|
One particular “up regulated” variant of interest is rs234706 or CBS C699T which I’ll discuss in more depth below.
CBS C699T and ammonia
For a very good, if not skeptical, overview on CBS upregulation via C699T (the gene with the most data), take a look at this article by Mark London at MIT.
Mark discusses the work of Dr. Amy Yasko, a doctor who believes CBS SNPs have an impact on autism, but in the context of studies that have measured homocysteine levels in C699T genotypes. Many of these studies have not shown significant decreases in homocysteine with the T allele, important because low homocysteine would be evidence of increased CBS activity. But lost in the shuffle in many discussions surrounding CBS is ammonia, because it’s ammonia that is a byproduct of sulfur metabolism. The practical implication for the everyday person with CBS gene SNPs would seem to be not only low homocysteine, but also awareness of elevated ammonia, regardless of whether the CBS SNP actually caused the ammonia level to rise (or whether it was the CBS genes working on concert with Urea Cycle SNPs).
But how best to test for ammonia?
To quote Mark:
Urinary ammonia is an even less reliable method for testing for CBS upregulation. This is because most of the ammonia (NH4+) in urine is produced by the kidneys for ph regulation. The ammonia that is produced elsewhere in the body, is usually detoxified by being converted to urea, which is then excreted. This process mainly occurs in the liver, and the liver is quite capable of handling the large amount of ammonia that is produced in the body, which occurs due to the metabolization of amino acids. The liver has to be able to do this, because the nervous system can only tolerate very low levels of ammonia. Excess ammonia, i.e., hyperammonia, only usually occurs either when liver functioning has been greatly reduced, or where a genetic defect in the urea cycle exists. Only by testing serum ammonia, can such a condition be diagnosed.
In light of the prevalence of these CBS gene variants, especially C699T, which has the most science examining up regulation, it seems unlikely to me that most people should be taking extreme measures with their diets as the result of heterozygous CBS SNPs. However, I must caution, that I am not a doctor (although how many doctors know a thing about nutrigenomics).
My observation is rooted in common sense. Would 28% of the population really have to avoid sulfur rich foods?
I think it’s fair to say that there is quite a bit of confusion out there on this topic from all sides, but in my case, when I read my charts, and as I’ve mentioned above, I’m looking to interpret CBS SNPs along side other relevant SNPs that could lead to an overload of ammonia on the nervous system.
Having said that, this does not mean that changes in the CBS gene enzyme would not have any impact on how people process and respond to sulfur, especially sulfur donor supplements which give a mega-dose of sulfur in pill form.
My practical focus for CBS – homocysteine and ammonia awareness
I have a couple heterozygous SNPs for two CBS variants, but not for C699T. For me, the most interesting aspect of the CBS discussion centers around homocysteine and ammonia awareness.
Regardless of causation, maybe it’s the CBS SNPs that cause low or high homocysteine, maybe it isn’t, we know that elevated homocysteine levels are linked with a number of bad health outcomes, and that low homocysteine is not necessarily a good thing either.
I find it fascinating that sulfur metabolism has an impact on ammonia levels, which were not on my radar prior to looking into the CBS SNPs. Of course, sulfur isn’t the only thing that causes elevated ammonia, but a deep dive into the topic has the potential to add a layer of sophistication to a nutrition plan.
Per Mark London’s article, if you are planning on testing your ammonia levels, it appears a serum test (performed fasted) is the best route.
However, for my next post, I will take a look at the urea cycle, and how it has the potential to impact the body’s ability to get rid of ammonia.
You can read that post, which is very long, here.