Cannabinoid receptor variant may be therapeutic target in pediatric IBD

A functional variant, Q63R, in cannabinoid receptor type 2 (CB2) contributes to pediatric inflammatory bowel disease (IBD) susceptibility, particularly Crohn’s disease (CD), Italian investigators have found.

Impaired functionality of the CB2 receptor may dampen suppression of activated macrophages and stimulate the secretion of proinflammatory cytokines to exacerbate intestinal inflammation and worsen IBD, they proposed.

“Taken together, our data point toward the involvement of the CB2 receptor in the pathogenesis and clinical features of pediatric IBD,” the researchers wrote in the Journal of Clinical Gastroenterology. The findings point to a potential therapeutic target, they added.

For this study, the investigators genotyped a cohort of 217 children with IBD (112 with CD and 105 with ulcerative colitis [UC]) and 600 controls for the CB2-Q63R variant. The genotype frequency for the CB2-Q63R variant was significantly different in the IBD children compared with the controls (P=0.0006), both for children with CD (P=0.00005) and those with UC (P=0.03), reported first author Caterina Strisciuglio, MD, PhD, Second University of Naples, Caserta, Italy, and colleagues.

The researchers also found a high prevalence (50%) of the GG/GG genotype in IBD children with the CB2-Q63R variant compared with controls (32%).

Separately, the RR genotype was significantly overrepresented, with increased susceptibility to IBD (OR 1.82, P=0.0002), CD (OR 2.02, P=0.001), and UC (OR 1.63, P=0.02) for RR homozygous subjects. The risk for developing CD was significantly higher (OR 6.92, P=0.0002) with the presence of at least one GG-allele (homozygous RR plus heterozygous QR vs QQ subjects).

In both children with CD and UC, the R63 variant was strongly associated with moderate-to-severe activity of the disease at diagnosis, as determined by scores on the Pediatric Crohn’s Disease Activity Index and the Pediatric UC Activity Index (PUCAI).

“Moreover, in UC patients, the CB2-R63 variant was associated with a higher incidence of early clinical relapse, and homozygous RR patients showed a three-fold increased risk of presenting with a PUCAI score >35 at diagnosis (P=0.01), further suggesting an association with a more severe phenotype of the disease,” the investigators noted.

On multivariate logistic regression, all of the clinical features of UC related to the CB2 risk allele were still significantly associated with the variant (P=0.001).

These findings “support the concept that the CB2 receptor on immune effector cells may represent a potential target for selective CB2 agonist therapies, which could suppress proinflammatory and immune responses,” they wrote. “The fact that there is a CB2 stimulating compound already in clinical practice makes us more confident that this may be a new therapeutic option and a viable type of intervention in IBD.”

The increased incidence of IBD in childhood signifies the importance of this research, the investigators noted. “In a pediatric population with IBD, genetic susceptibility could be greater than environmental exposure and could influence a more severe disease course, making genetic investigations in pediatric IBD populations rewarding,” they wrote. 

They called for additional study to understand how the Q63R variant contributes to pediatric IBD susceptibility, and whether this variant represents a new disease marker.