The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction
The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction
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DOI：
10.1007/s00439-006-0250-x
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发表时间：
2006-11-01
期刊：
影响因子：
5.3
通讯作者：
Sipe, Jack C.
中科院分区：
文献类型：
--
作者：
Flanagan, Jonathan M.;Gerber, Alexandra L.;Sipe, Jack C.
人脂肪酸酰胺水解酶（FAAH）错义突变c.385 C -> A导致保守的脯氨酸残基转化为苏氨酸（P129 T），其与街头毒品使用和问题药物滥用相关。虽然FAAH P129 T变异与人类药物滥用之间的联系已被报道，但风险程度和物质成瘾脆弱性的具体类型仍有待确定。在此，我们调查了FAAH P129 T变异与一些连锁单核苷酸多态性的关系，以建立单体型系统，计算FAAH 385 C -> A突变的估计年龄和起源，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，使用逻辑回归分析控制种族，与相同种族背景的无药物个体相比，249名记录有多种不同药物成瘾的受试者中FAAH P129 T纯合子的显著过度代表性（P = 0.05）。为了通过增加样本量来增加逻辑回归分析能力，将来自我们先前研究的数据（Sipe等人，Proc Natl Acad Sci USA 99：8394-8399，2002）与本队列合并，其将显著性增加至P = 0.00003。对多个不同药物成瘾者和对照受试者中P129 T变异体的FAAH染色体背景的调查揭示了共同的祖先单倍型，单倍型遗传多样性的显著群体差异和估计的P129 T突变年龄为114，425 - 177，525岁。总的来说，这些结果表明，P129 T突变是FAAH基因中唯一常见的突变，并与成瘾性状显着相关。此外，这种突变似乎出现在人类进化的早期，这项研究验证了FAAH P129 T变异体与多种不同药物成瘾之间的联系。
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.