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

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.

FAAH Pro129Thr Variant Is Associated with Increased Cholesterol Levels in Normal-Weight Metabolically Unhealthy Subjects.

Introduction: The endocannabinoid system (ECS) plays an integral role in maintaining metabolic homeostasis, where an hyperactivation has been related with serum lipid alterations. The biological effects of ECS are limited by the activation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) and by polyunsaturated fatty acid (PUFA) intake as precursors. The FAAH Pro129Thr variant has been associated with obesity in some populations. However, the association with metabolic phenotypes in the Mexican population has not been studied. This study aimed to analyze the association of the FAAH Pro129Thr variant with serum lipids and diet in Mexican adults with different metabolic phenotypes. Methods: This is a cross-sectional study with 306 subjects between 18 and 65 years of age. They were classified with normal weight (NW) or excess weight (EW) according to their body mass index (BMI). The EW group included individuals with overweight or obesity (BMI 25-39.9 kg/m2). The individuals were classified into two metabolic phenotypes, metabolically healthy and metabolically unhealthy (MUH), using the homeostatic model assessment of insulin resistance and the National Cholesterol Education Program-adenosine triphosphate III cutoff points for blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. Subjects with ≥2 of 5 altered parameters were classified as MUH. The FAAH Pro129Thr variant was determined by allelic discrimination with TaqMan® probes. Results: The total cholesterol and very low-density lipoprotein cholesterol levels were associated with the FAAH Pro129Thr variant in NW-MUH subjects. Moreover, a lower PUFA intake was found in EW-MUH subjects with the FAAH variant. Conclusions: FAAH Pro129Thr variant has an important role in lipid metabolism, especially in NW-MUH subjects. By contrast, a low dietary intake of endocannabinoid PUFA precursors may partly counteract the development of the altered lipid profile associated with overweight/obesity.