The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: Studies of drug use and dependence in caucasians

Abstract

A genetic variation in fatty acid amide hydrolase (FAAH), C385A (P129T), has been previously associated with risk for problem street drug use. FAAH is a mammalian enzyme that inactivates neuromodulatory-signaling lipids including the endogenous cannabinoid 1 receptor agonist anandamide. We investigated in adult Caucasians (N = 749) whether this FAAH variant altered the risk for trying, regular use of or dependence on cannabis, alcohol or nicotine, traditional "gateway" drugs. Consistent with our knowledge that the A/A genotype results in reduced FAAH expression and activity in humans, subjects with the A/A genotype were less likely to be THC dependent than subjects with either a C/C or C/A genotype (11% vs. 26%, P < 0.05). No association was observed between the A/A genotype and risk for alcohol or tobacco regular use, or DSM IV dependence. Controlling for regular use of nicotine and sedatives, both identified as confounders, those with the A/A genotype were at significantly reduced risk for being THC dependent (OR 0.25, 95% CI: 0.07-0.88) as compared with those with the C/A or C/C genotype, supporting a link between alterations in the endocannabinoid system and THC dependence. Unexpectedly, we found an increased risk for regular use of sedatives among the A/A genotype group. The relationship between the FAAH A/A genotype and risk for drug dependence in this study was drug class specific, suggesting it is not part of a more general drug abuse effect. These results, particularly the observation of altered risk for sedative drug use, should be investigated further in multiple ethnic populations.

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

“…Among 80 individuals with drug abuse or alcoholism and over 1000 controls, the odds ratio for risk of combined street drug use and problem drug/alcohol use was 4.9 (95% CI: 2.5-9.7) in rs324420 AA individuals [50], and results were consistent and even more significant in a larger sample with mixed ethnicity [42]. In contrast, the C allele has also been associated with increased risk for progression to cannabis dependence, although this result has not yet been replicated [51].…”

Evaluating the Association of <i>FAAH</i> Common Gene Variation with Childhood, Adult Severe Obesity and Type 2 Diabetes in the French Population

“…In addition, FAAH mRNA expression in adipose tissue is negatively correlated with circulating endocannabinoid and visceral fat mass, and is increased in mature adipocytes compared with preadipocytes [11][12][13]. A functional missense polymorphism Pro129Thr has been associated with drug use [14][15][16] and with reduced cellular expression and activity of human FAAH in T lymphocytes and COS-7 cells [17]. In addition, the Pro129Thr polymorphism has been associated with overweight and obesity in a cohort of European and African ancestry, but this association was not confirmed in Asian [18] and was borderline associated with overweight in Danish population-based cohorts [19] but in the Key Words Genetics · Obesity · Type 2 diabetes…”

Scientific Opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin

“…A missense SNP, C385A (rs324420), results in a mutant form of FAAH with reduced expression and cellular stability (Chiang et al, 2004) and it has been shown that in marijuana users, the C allele of this SNP is associated with a higher risk for progression to cannabis dependence (Tyndale et al, 2007). Also Haughey et al (2008) reported an association between the C allele and craving after marijuana abstinence in young marijuana users.…”