title: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.
authors: Medical College of Wisconsin, Milwaukee, Wisconsin, WI 53226, USA.
authors: Yi
authors: Y
authors: Zhang
authors: Gabriele E
authors: GE
authors: Sonnenberg
authors: Tesfaye Mersha
authors: TM
authors: Baye
authors: Jack
authors: J
authors: Littrell
authors: Jennifer
authors: J
authors: Gunnell
authors: Ann
authors: A
authors: DeLaForest
authors: Erin
authors: E
authors: MacKinney
authors: Cecilia J
authors: CJ
authors: Hillard
authors: Ahmed H
authors: AH
authors: Kissebah
authors: Michael
authors: M
authors: Olivier
authors: Russell A
authors: RA
authors: Wilke
mesh_terms: D000581:Amidohydrolases / Q000235:genetics*; D001837:Body Weights and Measures; D050171:Dyslipidemias / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D005060:Europe; D005260:Female; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D044465:White People / Q000235:genetics*; D014922:Wisconsin; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D007328:Insulin; D000099252:Fatty Acid Amide Hydrolases