Genes ultimately determine your characteristics and many genes come in variants, which determine mostly subtle changes to these characteristics such as eye or hair color.
In a similar way, the genes that code for our endocannabinoid system/ECS come in variants, which can influence the way our ECS works.
By extension, ECS variation also determines which diseases we are likely to develop during our lives and can help predict how these diseases are best treated.
This section discusses known variations to the ECS and their impact in health and disease.
Table 1: summary of ECS gene variations associated with disease
Acute Respiratory Tract Infection
A missense mutation in CNR2 (Q63R) helps determine the severity of respiratory tract infection after Respiratory Syncytial Virus infection. Children carrying the Q allele were twice as likely to develop severe ARTI after RSV. Also, CB2 activation reduces disease severity while CB2 inhibition exacerbates disease progression (Tahamtan et al., 2017).
Affective working memory
A polymorphism in CNR1 (rs2180619, A>G) seems to influence affective working memory. People with the most prevalent A allele are biased towards remembering positive words rather than negative words. People with the G allele on the other hand have a better affective working memory in general (Fairfield et al., 2017).
In children with anxiety disorder several ECS gene polymorphisms were associated with poor treatment response: CNR1 rs806365, CNR1 rs7769940, CNR2 rs2501431, CNR2 rs2070956 and FAAH rs2209172 while the CNR1 rs6928813 polymorphism was associated with improved treatment response (Lester et al., 2016).
Blood THC level
ATP-binding cassette /ABC transporters are involved in shuttling many substances across the plasma membrane, including cannabinoids like THC. In ABCB1, the C3435T (rs1045642) was found to modulate serum THC levels in the sense that heavy cannabis users carrying the T allele had significantly lower THC levels (8 ng/ml) than CC homozygotes (15.7 ng/ml) (Kebir et al., 2017).
Variations the Cyp2C9 gene are associated with different THC metabolism. The Cyp2C9*2 was neutral to THC degradation but Cyp2C9*3 slowed THC degradation down threefold and decreased THC metabolite 11-COOH-THC levels by 70% compared to Cyp2C9*1 (Sachse-Seeboth et al., 2009).
Two polymorphisms for FAAH, rs324420 and rs4141964, were associated with an increased risk of developing cannabis dependence. For other ECS genes such as CNR1, MAGL and DAGL no such association was found (Melroy-Greif et al., 2016).
Carriers of the C allele for the CNR1 rs806374 polymorphism have an increased risk of developing cannabis dependence (Ashenhurst et al., 2017).
In other studies several other ECS polymorphisms were found to influence cannabis dependence: CNR1 rs806380 (disputed), CNR1 rs1049353 (in Caucasians), ABCB1 rs1045642 CC genotype, COMT rs4680 (association with psychotic symptoms), GABRA2 rs279858 A231G and NRG1 rs17664708 (reviewed in: Hryhorowicz et al., 2017).
Several mutations of CNR1, G1359A and A1359A had higher HDL cholesterol and lower blood triglycerides than wildtype G1359G which is associated with reduced cardiovascular risk (de Luis et al., 2016).
Cyclic vomiting syndrome/Migraine
There is an increased risk of developing cyclic vomiting syndrome for people carrying the G allele of the CNR1 rs806380 polymorphism and a reduced risk for people with the CC phenotype for CNR1 rs806368 or those carrying the G allele of the rs1799971 polymorphism of the Mu-opioid receptor (Wasilewski et al., 2017). In addition, the Mu-opioid receptor rs1799971 G allele and the CNR1 rs806368 C allele were associated with Migraine. The C allele of CNR1 rs2023239 was associated with positive outcome of treatment (Wasilewski et al., 2017).
Cytochrome P450 enzymes
Cytochrome P450 enzymes are involved in the oxidation of many exogenous and endogenous substances including plant and endocannabinoids. Across the world population many variations exist within the cytochrome P450 that affect cannabinoid metabolism and therefore many ECS-related diseases. These variations are listed in http://www.ghmedical.com/endocannabinoid-system/synthesizing-degrading-enzymes/cytochrome-p450.
A CNR1 mutation, G1359A is associated with esophageal cancer, with the A allele being more prevalent in tissue samples from cancer patients and the A allele being negatively correlated with survival time (Bedoya et al., 2009).
The G allele of CNR1 G1359A is associated with a lower susceptibility to glioma (Núñez et al., 2010). Interestingly, this mutation is also associated with reduced cardiovascular risk (de Luis et al., 2016).
One polymorphism in CNR1, rs806377, is associated with subjective happiness with carriers of the C allele responding stronger to positive stimuli and experiencing a higher subjective happiness level than homozygous carriers of the T allele (Matsunaga et al., 2014).
HIV/Hepatitis C co-infection
The CNR2 polymorphism rs35761398 was investigated in patients with HIV/Hepatitis C co-infection. Patients with the R allele being significantly more associated with inflammatory liver damage than the Q allele (Sagnelli et al., 2017).
Irritable bowel syndrome/IBS
The CNR1 gene encoding CB1 varies in the amount of AAT triplet repeats. People with more than 10 AAT repeats had a significantly higher risk of developing IBS than people with fewer AAT repeats (Jiang et al., 2014).
However, no correlation was found between the number of AAT triplets and the disease phenotype: constipation, diarrhea or mixed (Camilleri et al., 2013).
The CNR1 rs806378 mutation is associated with disease phenotype (Camilleri et al., 2013).
Variation in FAAH (rs324420, C385A), was found to be associated with irritable bowel syndrome and IBS-diarrhea and IBS-alternating in particular (Camilleri et al., 2008), although this is disputed (Jiang et al., 2014).
The rs806366 polymorphism of CNR1 is associated with increased headache with nausea after stressful events but not with Migraine per se (Juhasz et al., 2016).
Multiple Sclerosis treatment with interferon-beta is often discontinued when patients develop the ‘flu-like syndrome’. Patients with the GG genotype of the TRPV1 rs222747 polymorphism report greater pain and weakness during flu-like syndrome and are thus more likely to discontinue interferon-beta treatment (Buttari et al., 2017).
Non-alcoholic Fatty Liver Disease/NAFLD
NAFLD is often associated with Polycystic Ovary Syndrome/PCOS. The G allele of CNR1 rs806381 and the GG phenotype of rs10485170 were significantly higher in women with PCOS and NAFLD than in PCOS women without NAFLD (Kuliczkowska Plaksej et al., 2014).
There is an association between obesity and the rs3123554 polymorphism in the CNR2 gene. Genotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers (de Luis et al., 2017).
Similarly, the CNR1 polymorphism rs806381 was associated with increased visceral fat and rs1049353 with increased visceral and intermuscular fat (Frost et al., 2010).
The G1422A polymorphism of CNR1 is associated with increased abdominal fat in men (but not women)(Peeters et al., 2007).
In post-menopausal women the rs4237 and rs2501431 polymorphisms of CNR2 were associated with bone mineral density and osteoporosis (Zhang et al., 2015).
N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme, hydrolyzing various bioactive N-acylethanolamines with a preference for palmitoylethanolamide. In the human Prostate cancer cell line LNCaP, four splice variants were found. Two of these splice variants, b2 and c2, form catalytically inactive, truncated proteins which may be associated with the risk of developing Prostate cancer (Sakura et al., 2016).
Ashenhurst, J.R., Harden, K.P., Mallard, T.T., Corbin, W.R., and Fromme, K. (2017). Developmentally Specific Associations Between CNR1 Genotype and Cannabis Use Across Emerging Adulthood. J. Stud. Alcohol Drugs 78, 686–695.
Bedoya, F., Meneu, J.C., Macías, M.I., Moreno, A., Enríquez-De-Salamanca, R., Gonzalez, E.M., and Vegh, I. (2009). Mutation in CNR1 gene and VEGF expression in esophageal cancer. Tumori 95, 68–75.
Buttari, F., Zagaglia, S., Marciano, L., Albanese, M., Landi, D., Nicoletti, C.G., Mercuri, N.B., Silvestrini, M., Provinciali, L., Marfia, G.A., et al. (2017). TRPV1 polymorphisms and risk of interferon β-induced flu-like syndrome in patients with relapsing-remitting Multiple Sclerosis. J. Neuroimmunol. 305, 172–174.
Camilleri, M., Carlson, P., McKinzie, S., Grudell, A., Busciglio, I., Burton, D., Baxter, K., Ryks, M., and Zinsmeister, A.R. (2008). Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G13-19.
Camilleri, M., Kolar, G.J., Vazquez-Roque, M.I., Carlson, P., Burton, D.D., and Zinsmeister, A.R. (2013). cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G553-560.
Fairfield, B., Mammarella, N., Franzago, M., Di Domenico, A., Stuppia, L., and Gatta, V. (2017). A variant on promoter of the cannabinoid receptor 1 gene (CNR1) moderates the effect of valence on working memory. Mem. Hove Engl. 1–9.
Frost, M., Nielsen, T.L., Wraae, K., Hagen, C., Piters, E., Beckers, S., De Freitas, F., Brixen, K., Van Hul, W., and Andersen, M. (2010). Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution. Eur. J. Endocrinol. 163, 407–412.
Hryhorowicz, S., Walczak, M., Zakerska-Banaszak, O., Słomski, R., and Skrzypczak-Zielińska, M. (2017). Pharmacogenetics of cannabinoids. Eur. J. Drug Metab. Pharmacokinet.
Jiang, Y., Nie, Y., Li, Y., and Zhang, L. (2014). Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J. Gastroenterol. Hepatol. 29, 1186–1191.
Juhasz, G., Csepany, E., Magyar, M., Edes, A.E., Eszlari, N., Hullam, G., Antal, P., Kokonyei, G., Anderson, I.M., Deakin, J.F.W., et al. (2016). Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress. Genes Brain Behav.
Kebir, O., Lafaye, G., Blecha, L., Chaumette, B., Mouaffak, F., Laqueille, X., and Benyamina, A. (2017). ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users. Psychiatry Res.
Kuliczkowska Plaksej, J., Laczmanski, L., Milewicz, A., Lenarcik-Kabza, A., Trzmiel-Bira, A., Zaleska-Dorobisz, U., Lwow, F., and Hirnle, L. (2014). cannabinoid receptor 1 gene polymorphisms and nonalcoholic Fatty liver disease in women with polycystic ovary syndrome and in healthy controls. Int. J. Endocrinol. 2014, 232975.
Lester, K.J., Coleman, J.R.I., Roberts, S., Keers, R., Breen, G., Bögels, S., Creswell, C., Hudson, J.L., McKinnon, A., Nauta, M., et al. (2016). Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet.
de Luis, D.A., Ballesteros, M., Lopez Guzman, A., Ruiz, E., Muñoz, C., Penacho, M.A., Iglesias, P., Maldonado, A., San Martin, L., Izaola, O., et al. (2016). Polymorphism G1359A of the cannabinoid receptor gene (CNR1): allelic frequencies and influence on cardiovascular risk factors in a multicentre study of Castilla-Leon. J. Hum. Nutr. Diet. Off. J. Br. Diet. Assoc. 29, 112–117.
de Luis, D.A., Izaola, O., Primo, D., de la Fuente, B., and Aller, R. (2017). Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects. Endocrinol. Diabetes Nutr. 64, 440–445.
Matsunaga, M., Isowa, T., Yamakawa, K., Fukuyama, S., Shinoda, J., Yamada, J., and Ohira, H. (2014). Genetic Variations in the Human cannabinoid Receptor Gene Are Associated with Happiness. PLOS ONE 9, e93771.
Melroy-Greif, W.E., Wilhelmsen, K.C., and Ehlers, C.L. (2016). Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans. Drug Alcohol Depend.
Núñez, M., Perdomo, S., Moreta, J., Santos-Briz, Á., and González-Sarmiento, R. (2010). The G1359A-CNR1 gene polymorphism is associated to glioma in Spanish patients. Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. cancer Inst. Mex. 12, 825–828.
Peeters, A., Beckers, S., Mertens, I., Van Hul, W., and Van Gaal, L. (2007). The G1422A variant of the cannabinoid receptor gene (CNR1) is associated with abdominal adiposity in obese men. Endocrine 31, 138–141.
Sachse-Seeboth, C., Pfeil, J., Sehrt, D., Meineke, I., Tzvetkov, M., Bruns, E., Poser, W., Vormfelde, S.V., and Brockmöller, J. (2009). Interindividual variation in the pharmacokinetics of Delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin. Pharmacol. Ther. 85, 273–276.
Sagnelli, C., Uberti-Foppa, C., Hasson, H., Bellini, G., Minichini, C., Salpietro, S., Messina, E., Barbanotti, D., Merli, M., Punzo, F., et al. (2017). cannabinoid receptor 2-63 RR variant is independently associated with severe necroinflammation in HIV/HCV coinfected patients. PloS One 12, e0181890.
Sakura, Y., Tsuboi, K., Uyama, T., Zhang, X., Taoka, R., Sugimoto, M., Kakehi, Y., and Ueda, N. (2016). A quantitative study on splice variants of N-acylethanolamine acid amidase in human Prostate cancer cells and other cells. Biochim. Biophys. Acta 1861, 1951–1958.
Spagnolo, P.A., Ramchandani, V.A., Schwandt, M.L., Kwako, L.E., George, D.T., Mayo, L.M., Hillard, C.J., and Heilig, M. (2016). FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence. Alcohol. Clin. Exp. Res.
Tahamtan, A., Samieipoor, Y., Nayeri, F.S., Rahbarimanesh, A.A., Izadi, A., Rashidi-Nezhad, A., Tavakoli-Yaraki, M., Farahmand, M., Bont, L., Shokri, F., et al. (2017). Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. Virulence 0.
Wasilewski, A., Lewandowska, U., Mosinska, P., Watala, C., Storr, M., Fichna, J., and Venkatesan, T. (2017). cannabinoid Receptor Type 1 and mu-Opioid Receptor Polymorphisms Are Associated With Cyclic Vomiting Syndrome. Am. J. Gastroenterol.
Zhang, C., Ma, J., Chen, G., Fu, D., Li, L., and Li, M. (2015). Evaluation of common variants in CNR2 gene for bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese. Osteoporos. Int. J. Establ. Result Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA 26, 2803–2810.