Section on Human Psychopharmacology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
Addict Biol. 2018 Jan;23(1):474-484. doi: 10.1111/adb.12491. Epub 2017 Feb 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 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.
内源性大麻素系统在奖赏和成瘾中起着重要作用。两种主要的内源性大麻素神经递质之一，花生四烯酸乙醇胺，被脂肪酸酰胺水解酶代谢，这种酶具有功能性遗传多态性（FAAH Pro129Thr，rs324420）。Thr129 等位基因与药物和酒精使用问题有关，但这种关联尚未得到广泛复制，并且可能与严重程度的临床测量而不是分类诊断的关联更强。在本研究中，我们试图确定 Thr129 等位基因是否与欧洲裔美国人和非裔美国人 1434 名个体中的酒精依赖（AD）诊断和严重程度有关，其中 952 名被诊断为终生 AD。参与者被 FAAH rs324420 进行了基因分型，并且通过全基因组祖先信息标记面板确定了祖先。受试者参加了精神障碍的结构临床访谈和 90 天时间线随访访谈，以评估最近的酒精使用情况。当前患有 AD 的欧洲裔美国人的 Thr129 等位基因频率高于非依赖性对照组。在患有终生 AD 的欧洲裔美国人中，两种基因型组之间的饮酒天数和狂欢饮酒天数存在显着不同的分布，携带 Thr129 的个体报告的中位数比 Pro129/Pro129 纯合子少 10 天的戒酒天数和多 13 天的狂欢饮酒天数。在非裔美国人参与者中，病例和对照组之间的 Thr129 等位基因频率没有显着差异，基因型之间的 AD 严重程度也没有显着差异。这些发现提供了证据表明 Pro129Thr 错义变体与欧洲裔美国人的 AD 严重程度有关。
