Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent. Pharmacogenomics 2009 Dec;10(12):1929-39
Date
12/05/2009Pubmed ID
19958092Pubmed Central ID
PMC3003434DOI
10.2217/pgs.09.122Scopus ID
2-s2.0-73649131984 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
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.
Author List
Zhang Y, Sonnenberg GE, Baye TM, Littrell J, Gunnell J, DeLaForest A, MacKinney E, Hillard CJ, Kissebah AH, Olivier M, Wilke RAAuthor
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmidohydrolasesBody Weights and Measures
Dyslipidemias
Europe
Female
Genotype
Glucose Tolerance Test
Humans
Insulin
Lipid Metabolism
Male
Middle Aged
Obesity
Pedigree
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Wisconsin
