A Genetic Variant in the Endocannabinoid System May Protect Against Priapism in Sickle Cell Disease | Research

The takeaway

In Brazilian sickle cell anemia patients, a specific CB2 receptor genetic variant (TT-CC genotype) was associated with 61% lower odds of developing priapism — suggesting the endocannabinoid system helps regulate this painful complication.

Read this if you have sickle cell disease or treat SCA patients — this genetic finding opens a new avenue for understanding and potentially preventing priapism.

What the researchers found

Sickle cell anemia (SCA) is a genetic blood disorder that causes a range of severe complications, including priapism — prolonged, painful erections caused by sickled red blood cells blocking penile blood vessels. Priapism affects up to 42% of males with SCA and can cause permanent damage, yet treatment options are limited.

This study investigated whether genetic variations in the endocannabinoid system (ECS) — the same system that cannabis acts on — might influence who develops priapism and who doesn't. The researchers genotyped 138 SCA patients (80 with priapism, 58 without) for four genetic variants: one each in the FAAH enzyme, the MAGL enzyme, the CB1 receptor, and the CB2 receptor.

The standout finding: the TT-CC genotype of the CB2 receptor variant (rs35761398) was associated with 61.4% lower odds of developing priapism (OR = 0.386) and a 36.6% lower risk over time (HR = 0.634). This suggests that the CB2 receptor — the cannabinoid receptor primarily expressed in immune and blood cells — plays a role in the vascular events that cause priapism in SCA.

The biological mechanism makes sense: the endocannabinoid system is involved in blood vessel relaxation, platelet aggregation, and immune responses — all of which are dysregulated in sickle cell priapism. A CB2 receptor variant that modulates these processes could protect against the vascular blockage that triggers priapism.

Alpha-thalassemia mutations were also less common in patients with priapism, consistent with their known protective effect against SCA complications.

Why it matters

This is one of the first studies to connect endocannabinoid system genetics to a specific clinical complication of sickle cell disease. If the CB2 receptor influences priapism risk, it raises the possibility that CB2-targeted medications (or even specific cannabinoids) could help prevent or treat this devastating complication. For the approximately 100,000 Americans with SCA, new therapeutic targets are urgently needed.

The numbers in context

138 SCA patients: 80 with priapism, 58 without. CB2 rs35761398 TT-CC genotype: OR = 0.386 (95% CI: 0.175–0.854, p = 0.019) for priapism; HR = 0.634 (95% CI: 0.402–0.987, p = 0.049) for time to priapism. Alpha-thalassemia was significantly less common in priapism patients (p < 0.001).

How the study worked

Observational genetic association study of 138 Brazilian sickle cell anemia patients (80 with priapism, 58 without). SCA confirmed by HPLC and PCR-RE for Hb SS genotype. Alpha-thalassemia detected with Multiplex-PCR. Four endocannabinoid system SNPs genotyped using TaqMan assays: FAAH rs324420, MAGL rs604300, CNR1 rs7766029, CNR2 rs35761398. Association assessed with multivariate logistic regression and Cox regression.

Who was studied

N=138 adults with sickle cell anemia, Brazil, 58 without priapism and 80 with priapism

What this study cannot tell us

Relatively small sample size (138 patients) for a genetic association study. Single-center Brazilian cohort — genetic frequencies may differ in other populations (African, Caribbean, South Asian). Association doesn't prove causation — the CB2 variant may be in linkage disequilibrium with another causal variant. Only four ECS polymorphisms were tested; other ECS genetic variations may also be relevant. Priapism status was based on clinical records, and subclinical episodes may have been missed.

How to read the evidence

Observational genetic association study with appropriate multivariate analysis. The sample size is modest for a genetics study, and the findings need replication in larger, independent cohorts. The biological plausibility (ECS role in vascular regulation) supports the association.

When this study was published

Published in 2024. This is an early finding in a niche area — replication studies may not yet exist.

The bigger picture

This study reveals the endocannabinoid system as a player in vascular complications beyond the brain and immune system. Most ECS research focuses on neurological and psychiatric effects — this finding in sickle cell disease highlights the system's role in blood vessel and hematological regulation. It adds an unexpected dimension to the RethinkTHC database and raises the question of whether cannabinoid-based treatments could have hematological applications.

Replication

Not stated in abstract.

Funding

Not reported in abstract.

Conflicts of interest

Not reported in abstract.

Questions still open

Could CB2 receptor agonists prevent priapism in SCA patients? Would cannabis use (which activates CB2 among other targets) affect priapism risk in SCA patients? Can these genetic findings be replicated in African and other SCA populations? Should ECS genotyping be incorporated into risk assessment for SCA complications?

Read the original research

The endocannabinoid system's genetic polymorphisms in sickle cell anemia patients.

Scientific reports, 14(1), 31562

Scientific Reports is a reputable journal known for publishing high-quality research across various scientific disciplines.

View on PubMed ↗Publisher’s paper ↗

Citation

Berti, Amanda Cristina Meneguetti; de Castro, Vanessa da Silveira Ramos; Arcanjo, Gabriela Silva; da Silva Araujo, Aderson; Lucena-Araujo, Antonio Roberto; Bezerra, Marcos André Cavalcanti; Gazarini, Lucas; da Silva, Danilo Grünig Humberto; Belini-Júnior, Edis. (2024). The endocannabinoid system's genetic polymorphisms in sickle cell anemia patients.. Scientific reports, 14(1), 31562. https://doi.org/10.1038/s41598-024-76480-0