Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent.

UNLABELLED: 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.

Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index.

AIMS: In humans, genetic variation in endocannabinergic signaling has been associated with anthropometric measures of obesity. In randomized trials, pharmacological blockade at the level of the cannabinoid receptor 1 (CNR1) receptor not only facilitates weight reduction, but also improves insulin sensitivity and clinical measures of lipid homeostasis. We therefore tested the hypothesis that genetic variation in CNR1 is associated with common obesity-related metabolic disorders. MATERIALS & METHODS: A total of six haplotype tagging SNPs were selected for CNR1, using data available within the Human HapMap (Centre d'Etude du Polymorphisme Humain population) these included: two promoter SNPs, three exonic SNPs, and a single SNP within the 3'-untranslated region. These tags were then genotyped in a rigorously phenotyped family-based collection of obese study subjects of Northern European origin. RESULTS & CONCLUSIONS: A common CNR1 haplotype (H4; prevalence 0.132) is associated with abnormal lipid homeostasis. Additional statistical tests using single tagging SNPs revealed that these associations are partly independent of body mass index.