Obesity-Related Dyslipidemia Associated with FAAH , Independent of Insulin Response, in Multigenerational Families of Northern European Descent

Abstract

A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. Aims N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. Materials & methods Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained for the FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). Results A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. Conclusion Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.

A Common CNR1 (Cannabinoid Receptor 1) Haplotype Attenuates the Decrease in HDL Cholesterol That Typically Accompanies Weight Gain

“…Recently, a number of lipid and lipoprotein phenotypes have been associated with variability in CNR1 , and the eCB signaling pathway in general [4], [7]. Our data are consistent with these reports.…”

Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin

“…SNP rs324420 has been recently associated with increased serum triglycerides and reduced high-density lipoprotein cholesterol (HDLc) level among subjects in one of the largest family-based obesity study cohorts. 59 These results suggest that the defective FAAH protein may affect lipid homeostasis by modifying ECs levels, however, the mechanistic link between genetic variations in FAAH, ECs/CB1 signalling SNPs associated with extrapulmonary and pulmonary injury-related ARDS in Stage I (p≤0.0005) were tested for validation in Stage II using two different populations with indirect (Population I) and direct (Population II) lung injury as risk factor for ALI/ARDS. Both populations were genotyped with the Human 610-quad platform.…”

Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism

“…Furthermore, there are positive correlations between 2-AG and body mass index (BMI) (kg/m 2 ) [44], waist circumference, and intra-abdominal adiposity [43, 45]. This may be due to the activity of monoacylglycerol lipase (MGL), which primarily degrades 2-AG, not increasing with BMI [43, 45], though expression of FAAH, which is also capable of breaking down 2-AG [46], does increase with BMI [47]. This increase in 2-AG may also be a result of increased diacylglycerol lipase in obesity, which has been demonstrated in both animal [48, 49] and human adipocytes [50, 51], though this may be site specific [50] and influenced by dietary composition [52].…”