Association between the FAAH C385A variant (rs324420) and obesity-related traits: a systematic review.

Oscar David Lopez-Cortes, Francisco Trujillo-Sánchez, Erika Sierra-Ruelas, Erika Martinez-Lopez, Vincenzo Di Marzo, Barbara Vizmanos

Journal: International journal of obesity (2005) 2024;48(2):188-201

PMID: 38114812

Full Text on Nature Publishing Group View on PubMed

Abstract

BACKGROUND

Overweight and obesity are the consequence of a sustained positive energy balance. Twin studies show high heritability rates pointing to genetics as one of the principal risk factors. By 2022, genomic studies led to the identification of almost 300 obesity-associated variants that could help to fill the gap of the high heritability rates. The endocannabinoid system is a critical regulator of metabolism for its effects on the central nervous system and peripheral tissues. Fatty acid amide hydrolase (FAAH) is a key enzyme in the inactivation of one of the two endocannabinoids, anandamide, and of its congeners. The rs324420 variant within the FAAH gene is a nucleotide missense change at position 385 from cytosine to adenine, resulting in a non-synonymous amino acid substitution from proline to threonine in the FAAH enzyme. This change increases sensitivity to proteolytic degradation, leading to reduced FAAH levels and increased levels of anandamide, associated with obesity-related traits. However, association studies of this variant with metabolic parameters have found conflicting results. This work aims to perform a systematic review of the existing literature on the association of the rs324420 variant in the FAAH gene with obesity and its related traits.

METHODS

A literature search was conducted in PubMed, Web of Science, and Scopus. A total of 645 eligible studies were identified for the review.

RESULTS/CONCLUSIONS

After the identification, duplicate elimination, title and abstract screening, and full-text evaluation, 28 studies were included, involving 28 183 individuals. We show some evidence of associations between the presence of the variant allele and higher body mass index, waist circumference, fat mass, and waist-to-hip ratio levels and alterations in glucose and lipid homeostasis. However, this evidence should be taken with caution, as many included studies did not report a significant difference between genotypes. These discordant results could be explained mainly by the pleiotropy of the endocannabinoid system, the increase of other anandamide-like mediators metabolized by FAAH, and the influence of gene-environment interactions. More research is necessary to study the endocannabinoidomic profiles and their association with metabolic diseases.

Address: Licenciatura en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico.; Instituto de Nutrigenética y Nutrigenómica Traslacional, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico.; Canada Excellence Research Chair in Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Quebec, QC, G1V 4G5, Canada.; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval, Québec, QC, G1V 4G5, Canada.; Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, Université Laval, Québec, QC, G1V 4G5, Canada.; Doctorado en Ciencias de la Nutrición Traslacional, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico.; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico.; Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale Delle Ricerche (CNR), Pozzuoli, Italy.; Instituto de Nutrigenética y Nutrigenómica Traslacional, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico. [email protected].; Doctorado en Ciencias de la Nutrición Traslacional, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico. [email protected].; Departamento de Clínicas de Reproducción Humana, Crecimiento y Desarrollo Infantil, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico. [email protected].; Departamento de Disciplinas Filosófico, Metodológicas e Instrumentales, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44320, Mexico. [email protected].

DOI: 10.1038/s41366-023-01428-9