Amide hydrolase 385 A/A(P129T) variant: analysis of an ancient missense mutation

人类脂肪酸酰胺水解酶(FAAH)错义突变c.385C-&gt；A导致保守的脯氨酸残基转化为苏氨酸(P129T)，与街头吸毒和问题吸毒有关。虽然已经报告了FAAH P129T变异与人类药物滥用之间的联系，但风险程度和物质成瘾脆弱性的具体类型仍有待确定。在这里，我们调查了FAAHP129T变异与一些连锁的单核苷酸多态的关系，以建立单倍型系统，计算FAAH385 C-&GT；A突变的估计年龄和来源，并在病例对照研究中评估其与临床显著药物成瘾的相关性。结果显示，在249例有多种不同毒瘾记录的吸毒者中，FAAHP129T纯合子与相同种族背景的非吸毒者相比有显著差异(P=0.05)。为了通过增加样本量来增加Logistic回归分析的能力，我们以前的研究(Sipe等人)的数据。在Proc Natl Acad Sci USA中)与现在的队列合并，其显著性增加到P=0.00003。对多个不同吸毒者和对照组的P129T突变的FAAH染色体背景进行了调查，发现两个人的祖先都有共同的单倍型，单倍型遗传多样性存在显著的群体差异，估计P129T突变的年龄为114,425-177,525岁。总而言之，这些结果表明，P129T突变是FAAH基因中唯一常见的突变，并且与成瘾特征显著相关。此外，这种突变似乎发生在人类进化的早期，这项研究证实了FAAHP129T变异与多种不同药物成瘾易感性之间的先前联系。

The human fatty acid amide hydrolase (FAAH) missense mutation c.385 C-->A, which results in conversion of a conserved proline residue to threonine (P129T), has been associated with street drug use and problem drug abuse. Although a link between the FAAH P129T variant and human drug abuse has been reported, the extent of risk and specific types of substance addiction vulnerability remain to be determined. Here, we investigated the relationship of the FAAH P129T variant to a number of linked single nucleotide polymorphisms to establish a haplotyping system, calculate the estimated age and origin of the FAAH 385 C-->A mutation and evaluate its association with clinically significant drug addiction in a case control study. The results showed a significant over-representation of the FAAH P129T homozygotes in 249 subjects with documented multiple different drug addictions compared to drug free individuals of the same ethnic backgrounds (P = 0.05) using logistic regression analysis controlling for ethnicity. To increase the logistic regression analysis power by increasing the sample size, the data from our previous study (Sipe et al. in Proc Natl Acad Sci USA 99:8394-8399, 2002) were pooled with the present cohort which increased the significance to P = 0.00003. Investigation of the FAAH chromosomal backgrounds of the P129T variant in both multiple different drug addicted and control subjects revealed a common ancestral haplotype, marked population differences in haplotype genetic diversity and an estimated P129T mutation age of 114,425-177,525 years. Collectively, these results show that the P129T mutation is the only common mutation in the FAAH gene and is significantly associated with addictive traits. Moreover, this mutation appears to have arisen early in human evolution and this study validates the previous link between the FAAH P129T variant and vulnerability to addiction of multiple different drugs.