Abstract
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.
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References
Ammerman AJ, Cavalli-Sforza LL (1984) The Neolithic transition and the genetics of populations in Europe. Princeton University Press, Princeton
Bisogno T, De Petrocellis L, Di Marzo V (2002) Fatty acid amide hydrolase, an enzyme with many bioactive substrates. Possible therapeutic implications1. Curr Pharm Des 8:533–547
Boger DL, Sato H, Lerner AE, Hedrick MP, Fecik RA, Miyauchi H, Wilkie GD, Austin BJ, Patricelli MP, Cravatt BF (2000) Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. Proc Natl Acad Sci USA 97:5044–5049
Chiang K, Gerber AL, Sipe JC, Cravatt BF (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:1–7
Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124
Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147:281–288
Kan YW, Dozy AM (1980) Evolution of the hemoglobin S and C genes in world populations. Science 209:388–391
Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C, Boger DL, Cravatt BF (2004) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311:441–448
McKinney MK, Cravatt BF (2005) Structure and function of Fatty Acid amide hydrolase. Annu Rev Biochem 74:411–432
Mountain JL, Cavalli-Sforza LL (1997) Multilocus genotypes, a tree of individuals, and human evolutionary history. Am J Hum Genet 61:705–718
Mountain JL, Lin AA, Bowcock AM, Cavalli-Sforza LL (1992) Evolution of modern humans: evidence from nuclear DNA polymorphisms. Philos Trans R Soc Lond B Biol Sci 337:159–165
Nei M, Roychoudhury AK (1993) Evolutionary relationships of human populations on a global scale. Mol Biol Evol 10:927–943
Payseur BA, Nachman MW (2000) Microsatellite variation and recombination rate in the human genome. Genetics 156:1285–1298
Risch N, de Leon D, Ozelius L, Kramer P, Almasy L, Singer B, Fahn S, Breakefield X, Bressman S (1995) Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 9:152–159
SchneiderS, Roessli D, Excoffier L (2000) Arlequin: a software for population genetics data analysis. Ver 2.000
Sipe JC (2004) The brain endogenous cannabinoid sysem: a role in reward/craving of addiction? Med Hypotheses Res 1:1–10
Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA 99:8394–8399
Sipe JC, Waalen J, Gerber A, Beutler E (2005) Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond) 29:755–759
Tishkoff SA, Verrelli BC (2003) Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet 4:293–340
Ueda N, Puffenbarger RA, Yamamoto S, Deutsch DG (2000) The fatty acid amide hydrolase (FAAH). Chem Phys Lipids 108:107–121
Acknowledgments
This is manuscript number 18126-MEM from The Scripps Research Institute. These studies were supported by the National Institutes of Health grant DA 015749-01, the Stein Endowment Fund, and the Skaggs Clinical Scholars Program. This research was also partially supported by the intramural research program of NIH/NIDA.
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Flanagan, J.M., Gerber, A.L., Cadet, J.L. et al. The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction. Hum Genet 120, 581–588 (2006). https://doi.org/10.1007/s00439-006-0250-x
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DOI: https://doi.org/10.1007/s00439-006-0250-x