The influence of genetics on the endocannabinoid system gene expression and relevance for targeting reproductive conditions.

Background: Endocannabinoids are small lipid molecules that have critical roles in cellular proliferation and function. They are produced locally with their concentrations controlled via the endocannabinoid system (ECS). The important cellular functions of endocannabinoids have made them and the proteins that modulate their expression targets of potential interest for treatment in many different diseases including gynaecological conditions. There is significant evidence of heredity differences in the response to both exogenous and endogenous cannabinoids that hampers the identification of effective targets. Whether compounds targeting endocannabinoids will be effective therefore may rely on personal differences mediated through genetic architecture. To investigate the source of individual differences, we investigated the effects of genetic variants on the expression of the endocannabinoid system genes at both a systemic and individual tissue level with a particular focus on the female reproductive system and the endometrium.

Methods: We performed this analysis using publicly available datasets, including the 31,684 participants from the eQTLGen database and 838 donors to the GTEx database which includes 49 different sources of tissue, as well as an in-house database of 206 endometrial samples. Analysis of the eQTLGen data identified 22,020 eQTLs that influenced 43 of the selected 70 ECS genes.

Results: A comparison across 49 different tissues that included at least 70 different individuals in the GTEx dataset identified eQTL for 69 of the 70 different genes, confirming a tissue-specific influence. Comparisons among 11 different physiological system indicated that the female reproductive system was associated with a fewer number of eQTLs. Finally, in the endometrium, we detected Bonferroni significant genetic effects on one individual gene fatty acid binding protein 3 (FABP3), an intracellular transporter that delivers endocannabinoids to the enzyme responsible for its inactivation, with a further 14 independent FDR significant eQTL for 13 ECS genes.

Conclusions: This is the first study to investigate the effects of genetic variants on the ECS gene transcription and indicates genetic variants have significant influence that are unique to each tissue. Our results highlight the effect of individual variation and the impact endocannabinoid based therapies may have on different tissue and physiological systems.