Repercussões de variantes genéticas em componentes do sistema endocanabinoide e no receptor PPAR-α sobre o perfil de risco cardiometabólico, adipocitocinas e níveis plasmáticos de endocanabinoides em indivíduos com diferentes graus de adiposidade

Abstract

To analyze the reciprocal association of cardiometabolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAH gene] and endocannabinoid receptor CB1 [CNR1 gene]) and the PPAR-α receptor (PPARA gene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI &#8805; 30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2 (n = 54), 27 men and 27 women; grade 2, with BMI between &#8805; 35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI &#8805; 40 kg/m2 (n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH 385C>A, CNR1 3813G>A and PPARA 484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study. The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance. The levels of PEA negatively associated with visceral adiposity and insulin resistance, suggesting a better metabolic profile, whereas 2-AG levels were positively associated with hsCRP, pointing to a worse metabolic profile. The polymorphisms studied were not associated with the obese or insulin resistant phenotype. The presence of the allele 3813G in the CNR1 gene was independently associated with reduced levels of adiponectin in obese patients, suggesting a worse metabolic profile in this group. The presence of the allele 484G in the PPARA gene associating with higher levels of BMI and LDL-cholesterol in eutrophics may indicate a predisposition for the development of obesity and atherosclerotic dyslipidemia in these individuals. The homozygous genotype AA in position 385 of the FAAH gene, along with levels of hsCRP, were the main direct and independent associations with AEA levels, clearly indicating dysfunction of the degradation enzyme of AEA and possibly contributing to a more vulnerable cardiometabolic profile in individuals with this variant genotype.