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Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant.

ABSTRACT: The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we sought to determine whether the Thr129 allele was associated with both alcohol dependence (AD) diagnosis and severity in a sample of 1434 European American and African American individuals, 952 of whom were diagnosed with lifetime AD. Participants were genotyped for FAAH rs324420, and ancestry was determined via a genome-wide panel of ancestry informative markers. Subjects participated in Structured Clinical Interviews for psychiatric disorders and 90-day Timeline Followback interviews to assess recent alcohol use. European American participants with current AD had a higher Thr129 allele frequency than non-dependent controls. In European Americans with lifetime AD, there were significantly different distributions of drinking days and binge drinking days between the two genotype groups, with Thr129 carriers reporting a median of 10 fewer abstinent days and 13 more binge drinking days than Pro129/Pro129 homozygotes. In African American participants, there were no significant differences between Thr129 allele frequency in cases and controls and no significant differences in measures of AD severity by genotype. These findings provide evidence that the Pro129Thr missense variant is associated with AD severity in European Americans.

SUBMITTER: Sloan ME

PROVIDER: S-EPMC5538894 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant.

Sloan Matthew E ME Gowin Joshua L JL Yan Jia J Schwandt Melanie L ML Spagnolo Primavera A PA Sun Hui H Hodgkinson Colin A CA Goldman David D Ramchandani Vijay A VA

Addiction biology 20170201 1

The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we so ...[more]

PMID: 28150397

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Project description:Purpose: Recent research has suggested that chronic alcohol exposure induces changes in the endocannabinoid system within the central nervous system and therefore could be an attractive target for better understanding and treating alcohol use disorder (AUD). Much of this research has centered around the CB1 receptor and its endogenous partial agonist, the endocannabinoid anandamide, as the CB1 receptor is densely expressed in brain regions involved in development and maintenance of addictive behaviors. In addition, recent evidence has suggested that chronic alcohol exposure induces changes in the modulation of endocannabinoid concentration and suggests that these changes may contribute to the motivation to abuse alcohol. Therefore, we performed a systematic literature review to evaluate how fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, relates to the characteristics and biology of AUD, as well as how modulating FAAH through pharmacologic inhibition or genetic manipulation affects outcomes related to alcohol use and consumption. Method: A search strategy was developed using the terms "endocannabinoids" or "drug delivery systems" and "alcohol dependence" or "alcohol use disorder" or "alcoholism" and "Fatty Acid Amide Hydrolase" and "FAAH" as text words and Medical Subject Headings (i.e., MeSH and EMTREE). We then used this search strategy on the electronic databases PubMed, Embase, and Web of Science. Results: We found 224 records; after removing repeated records (37%), articles that did not fit the topic question (47%), or were not primary research (4%), we included 26 for qualitative synthesis (12%). Discussion: The literature clearly suggests that FAAH has a role in the biology and characteristics of AUD. FAAH inhibition seems especially promising as a target for alcohol withdrawal as it may lead to a reduction in symptoms, including anxiety and a reduction of alcohol intake reinstatement. However, decreased FAAH may also lead to reduced sensitivity to alcohol along with increased preference and intake. Conclusions: Modulation of FAAH is promising for therapeutic intervention of AUD, but requires more research. Pre-clinical studies have indicated that FAAH inhibition may reduce withdrawal characteristics, but may also exacerbate other characteristics of AUD outside of that period.

Dataset Information

Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant.

Publications

Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant.

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