Can one SNP predispose to drug abuse?

[编者的话]

SNP的研究无论在生物信息学还是实验生物学中都一直是一个热点。但是在多大程度上SNP的差异可以造成疾病发生概率的显著不同呢？sipe等人的工作也许可以回答这一问题，他们的文章发表在最近的PNAS上，下文是对他们工作的评论。

The interactions between genes and behavior have been a hot issue of scientific debate for generations - you will perhaps recall those controversial studies with identical twins reared apart. The genome-behavior connection will definitely continue to attract attention and arouse public debate as the human genome continues to unfold its secrets. The implication of genetic factors in susceptibility to drug and alcohol abuse has always been at the focus of the public interest. A new study, bound to stir lasting debate, suggests that a very common exonic single nucleotide polymorphism (SNP) in the human gene coding for fatty acid amide hydrolase (FAAH) is strongly implicated in drug abuse. Jack Sipe and his colleagues from The Scripps Research Institute report that they have identified a natural exonic SNP in the FAAH gene, which is more common in its homozygous form among street drug users who also abuse alcohol compared with a control Caucasian population. Whereas this SNP was present in homozygous form in 4% of controls, nearly 16% of sampled street drug and/or alcohol abusers were found to be homozygous. This association seems highly relevant to drug abuse, as neither alcohol nor nicotine abuse alone showed any significant relationship to this SNP. Notably, statistical analysis, of paramount importance in genetic association studies, indicated that the differences were highly significant (p<0.001).

FAAH is responsible for the degradation of the endogenous cannabinoids (endocannabinoids) anandamide, 2-arachidonylglycerol and oleamide. The exonic SNP results in a missense mutation (385C-to-A) that converts a conserved proline residue to threonine (P129T), producing a FAAH variant that displays normal catalytic properties (Km and kcat ) towards anandamide and oleamide when expressed in transfected cells, yet is more susceptible to proteolytic degradation (~ twofold difference observed using the serine-protease trypsin).

The lower stability suggests that endogenous FAAH levels might be lower in P129T homozygous individuals, although this has yet to be established. Notably, it has been reported that transgenic mice lacking the FAAH gene have higher brain levels of anandamide. If a similar situation holds for humans, individuals homozygous for P129T might have higher brain levels of endocannabinoids. How this might affect predisposition to drug abuse is unclear, although one might suggest that brain circuitry formed when growing up with higher endogenous levels of endocannabinoids, implicated in reward mechanisms, might predispose the adolescent to seek unnatural gratification from illegal drug use.

The findings are of remarkable significance, going a long way beyond the issue of genetics in drug abuse, as the study is apparently the first one reporting that being different in just one SNP (on both genome copies) can have such a profound effect on a behavioral human trait. The diagnostic potential for identifying at-risk individuals is obvious. At the same time, perils of genetic testing-based discrimination come to mind, and many unresolved ethical issues are stirred.

相关文章请见：

Sipe J. C et al. (2002). A missense mutation in human fatty acid amide hydrolase associated with problem drug use. PNAS, 99:8394-8399.