Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity

Relationships of obesity degrees with (A) AEA, (B) 2-AG and (C) PEA levels.

<p>Values are medians (25^th, 75^th percentiles). Figures show medians and interquartile range. <i>P</i> values for trends of medians (Jonckheere-Terpstra test). *<i>P</i> = 0.04; **<i>P</i> = 0.003. AEA, anandamide; 2-AG, 2-arachidonoylglycerol; PEA, N-palmitoylethanolamide.</p

Main correlations of circulating endocannabinoids.

<p>Values are age- and sex-adjusted partial correlations with Bonferroni adjustment for multiple testing for a significance level < 0.05.</p><p>AEA, anandamide; PEA, palmitoylethanolamide; NS, non-significant.</p><p>Main correlations of circulating endocannabinoids.</p

Relationships of HOMA-IR tertiles with (A) AEA, (B) 2-AG and (C) PEA levels.

<p>Values are medians (25^th, 75^th percentiles). Figures show medians and interquartile range. <i>P</i> values for trends of medians (Jonckheere-Terpstra test). ^#<i>P</i> = 0.03; ^##<i>P</i> = 0.006; ^###<i>P</i> = 0.004. AEA, anandamide; 2-AG, 2-arachidonoylglycerol; PEA, N-palmitoylethanolamide.</p

Association of polymorphism <i>FAAH</i> 385C>A with AEA, OEA and HMW adiponectin levels.

<p>Values are medians (percentiles 25^th, 75^th).</p><p><i>P</i> values for differences in variables levels between AA and CC + CA genotypes (Mann-Whitney test).</p><p>Variables are age- and sex-adjusted.</p><p>AEA, anandamide; OEA, N-oleoylethanolamide; HMW adip, high molecular weight adiponectin.</p><p>Association of polymorphism <i>FAAH</i> 385C>A with AEA, OEA and HMW adiponectin levels.</p

Stepwise multiple linear regression of anandamide in the entire sample.

<p>b, regression coefficient; EP, standard error of regression coefficient b; β, standard regression coefficient. <i>P</i> value, statistical significance of regression coefficient b; 95% CI, 95% confidence interval for regression coefficient b.</p><p>BMI, body mass index; hsCRP, high sensitive C reactive protein; AA genotype, presence of homozygous genotype AA in position 385 of <i>FAAH</i>.</p><p>Stepwise multiple linear regression of anandamide in the entire sample.</p

Characteristics of the study population.

<p>Values are mean ± SD for variables with normal distribution or median (25^th; 75^th percentiles) for variables without normal distribution.</p><p><i>P</i> value for differences between variables in eutrophic and obese subjects.</p><p>M, male gender; F, female gender; HOMA-IR, homeostasis model assessment of insulin resistance; HMW adiponectin, high molecular weight adiponectin; hsCRP, high sensitive C reactive protein.</p><p>Characteristics of the study population.</p