The cannabinoid CB2 receptor is critical for limiting inflammation. Your risk of many immune diseases may be heightened if you have this genetic variant.
The clinical endocannabinoid deficiency hypothesis states that impairments in the endocannabinoid system (ECS) are responsible for a multitude of medical conditions. This could involve reduced levels of endocannabinoids, but also impaired receptor signaling.
The cannabinoid CB2 receptor is found on immune cells (although not exclusively) and its expression can increase rapidly during inflammation. This response appears to limit the extent of immune cell activation. But there are many pro- and anti-inflammatory signals…how do we know that the CB2 receptor has any real relevance in inflammatory diseases?
One way to examine this hypothesis is to study people who have genetic polymorphisms that cause reduced receptor expression or signaling. What luck! The CB2 receptor has a very common polymorphism that does this (well lucky for scientists, not so much for the patients).
It is called the Q63R polymorphism, since it causes the 63rd amino acid to change from a glutamine (Q) to an arginine (R). First reported in 2005, they found that endocannabinoids did not inhibit proliferation of immune cells nearly as much when they had the R version. Subsequent experiments showed that the R version had impaired signal transduction, particularly activation of ERK, an important signaling molecule in immune cells.
So how does having this impaired version of the CB2 receptor affect your risk of developing various immune-mediated diseases? What does this mean for the clinical endocannabinoid deficiency hypothesis? Read on to find out!
[Psst: EndoCanna Health will have a report on this polymorphism with their genetic test.]
1. Rheumatoid Arthritis
- Study of CNR2 Q63R gene polymorphism in Lebanese patients with rheumatoidarthritis (2018)
- Association between CNR2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis (2015)
- Reduced endocannabinoid immune modulation by a common CNR2 gene polymorphism (2005)
Rheumatoid arthritis is an autoimmune disease of the joints which you may be at higher risk of developing if you have an R allele. In a Lebanese study, having one R allele conferred a 3.9-fold higher risk and two R alleles conferred a 10.8-fold higher risk. Increased risk was also found in a 2005 pilot study of Caucasians, but the numbers were too small for adequate statistical analysis.
The childhood form of this disease, called juvenile idiopathic arthritis (JIA), also showed an increased risk to R carriers. The risk was 2.5-fold higher for the RR genotype. On top of this, RR genotype also doubled the risk of developing JIA before age 5 and increased the rate of disease relapse.
2. Celiac Disease
Celiac disease is a chronic inflammatory disease of the small bowel that occurs with the ingestion of gluten, found in several grains products. An association was found between Q63R and celiac disease, where having an RR genotype increased the risk of celiac disease by 6.1-fold relative to the QQ genotype.
3. Irritable Bowel Disease
- No association between the functional CNR2 Q63R variants and IBD in Turkish subjects (2014)
- CNR2 Functional Variant Contributes to the Risk for Pediatric IBD (2018)
Irritable bowel disease (IBD, also called IBS) is an inflammatory disease of the gastrointestinal tract. There are two main types, called Crohn’s disease and ulcerative colitis.
In an adult study, no relationship with Q63R was found for IBD. However, in a study of childhood IBD, the RR genotype confered a 1.8-fold higher risk for developing IBD, including both Crohn’s and ulcerative colitis. Patients with the RR genotype also had more severe IBD activity at diagnosis and earlier clinical relapse after treatment.
4. Immune Thrombocytopenic Purpura
- Role of CNR2 Polymorphism in Children with ITP in Beni-Suef Governorate in Egypt (2017)
- CNR2 polymorphism is associated with chronic childhood ITP in Egypt (2013)
- CNR2 functional variant (Q63R) influences childhood ITP (2011)
Thrombocytopenia is when you have low platelet counts, which reduces your clotting ability. Immune thrombocytopenic purpura (ITP) is an autoimmune disease that causes this. Three separate studies have looked at the contribution of Q63R to childhood ITP and all had consistent results. Having an RR genotype doubles the risk for developing ITP, and increases the risk of the chronic form by 2.3 to 2.9-fold.
5. Non-Alcoholic Fatty Liver Disease
- CNR2 functional variant influences liver damage in children with non-alcoholic fatty liver disease (2012)
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases common in obesity. Non-alcoholic steatohepatitis (NASH) is a more severe inflammatory form of NAFLD that can lead to cirrhosis. In obese children with NAFLD, R carriers were 5.3-fold more likely to develop NASH relative to subjects with the QQ genotype.
6. Viral Infections
- CNR2 63 QQ variant is associated with persistently normal aminotransferase levels in chronic HCV (2014)
- Association between a polymorphism in CNR2 and severe necroinflammation in patients with chronic HCV (2014)
- CB2-63 polymorphism and immune-mediated diseases associated with HCV chronic infection (2016)
- CNR2-63 RR variant is associated with necroinflammation in HIV/HCV coinfected patients (2017)
- Effects of CNR2 in respiratory syncytial virus infection in human subjects and mice (2018)
The CB2 receptor can be a double-edged sword when it comes to viral infections.
On one hand, CB2 activation inhibits immune cells, which can impair your ability to fight off a virus. For example, children with one type of acute respiratory tract infection were 2.1-fold more likely to develop a severe infection if they were a Q carrier.
On the other hand, too much immune cell activation can lead to damaging inflammation. For example, patients with a chronic HCV/HIV co-infection and an RR genotype were 2.9-fold more likely to have moderate-to-severe inflammatory liver damage relative to Q carriers.
7. Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disease that affects the myelin sheath of CNS neurons. Possible increased risk of developing MS with the Q63R polymorphism was found in a 2005 pilot study. Although the numbers were small, it was more common for MS patients to be a R carrier than healthy controls. Confirmation in future studies is necessary.
8. Lupus Erythematosus
Lupus is an autoimmune disease that can affect various bodily organs. A very small 2005 pilot study showed that out of 4 lupus patients, 3 were of the RR genotype. Although not statistically powered, this 75% rate of the RR genotype was much higher than the 32% found in control subjects. Confirmation in future studies is necessary.
9. Myasthenia Gravis
Myasthenia gravis is an autoimmune disease that affects the connection between the nerves and muscles, leading to muscular weakness. A very small 2005 pilot study showed that out of 6 myasthenia gravis patients, 5 were of the RR genotype. Although not statistically powered, this 83% rate of the RR genotype was much higher than the 32% found in control subjects. Confirmation in future studies is necessary.
Final note: As you can see from this list, many of the major inflammatory/autoimmune diseases have shown a link to the genetics of the CB2 receptor. I would not be surprised if even more are discovered soon. This is clearly one of the important regulators that can determine your risk for immune-mediated diseases.
If you have an impaired version of the CB2 receptor, it can be argued that you have a “clinical endocannabinoid deficiency” since your endocannabinoid system is not functioning optimally to limit inflammation. There are other polymorphisms (for example, in the endocannabinoid-degrading FAAH enzyme) that may contribute to this as well.
This polymorphism has also been linked to psychiatric diseases such as schizophrenia, depression, and addiction. Keep an eye out for a future article on this!
[And don’t forget: the genetic test at EndoCanna Health will have a report on this polymorphism.]