GENETIC VARIATION IN FATTY ACID AMIDE HYDROLASE (FAAH) IS
ASSOCIATED WITH ALTERED LIPID HOMEOSTASIS IN AN OBESE
COHORT
Y. Zhang1, E.M. Smith1, T. M. Baye1, J. Gunnell1, A. DelaForest3, C.J. Hillard3,
A.H. Kissebah1,4, M. Olivier1,2, and R.A. Wilke1,3,4
1
2
3
4
HMGC, Department of Physiology, Dept of Pharmacology, Dept of Medicine, medical College
of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
For centuries, marijuana (Cannabis sativa) has been an intriguing subject for its
psychoactive and medicinal effects in humans. Recent studies have revealed a
complicated network of endogenous cannabinoid (eCB) signaling pathways in which,
both exogenous and endogenous ligands act on a selective group of receptors, CB1 and
CB2 receptors. Two endogenous ligands, e.g. N-arachidonylethanolamine (AEA) and 2arachidonylglycerol (2-AG), have been identified for the CB1 receptor. Because these
lipid transmitters are not found to be kept in storage, but rather synthesized “on demand”,
fine-tuning of their levels relies on regulated turnover by two key enzymes, fatty acid
amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL).
Alterations in the eCB system are related to a variety of complex diseases including the
metabolic syndrome. Genetic and pharmacologic evidence support the hypothesis that
increased eCB/CB1 signaling over-rides the normal satiety signals to stimulate
inappropriate food consumption. Very recently, our group conducted association tests in
a family-based cohort using tag single nucleotide polymorphisms (tagSNPs) in the CB1
receptor gene (CNR1) (see poster by Mersha et al.). The tests revealed several
relationships between lipids and CNR1. CNR1 tagSNPs influence lipids directly,
independent of obesity.
In the current study, the contribution of FAAH gene to obesity-related lipid traits is being
characterized using a similar approach. Five FAAH tagSNPs representing linkage
disequilibrium within the entire FAAH gene region have been selected using the human
HapMap. We present here the preliminary data from one of these tagSNPs, a coding SNP
(cSNP; rs324420). As shown previously (Sipe 2005), we observed that this FAAH variant
is associated with body mass index (BMI). We also extend these observations, now
demonstrating that this cSNP is also associated with obesity-related lipid traits defining
the metabolic syndrome, i.e., high triglycerides and low HDL cholesterol.