Genetic variations in the enzymes involved in serotonin metabolism may contribute to a wide range of neuropsychiatric diseases, from eating disorders, obsessive-compulsive disorder and alcoholism to autism. Tryptophan, obtained only from the diet in humans, is converted to serotonin by tryptophan hydroxylase, or to kynurenine by tryptophan 2,3-dioxygenase (TDO2). Both enzymes are rate limiting in their respective pathways. The purpose of this study is to screen the TD02 gene for polymorphisms, assess functionality, and search for disease associations in 350 individuals. The original work was done using single-strand conformational polymorphism (SSCP) analysis. Most of the coding region (11 of the 12 exons) and short regions of the introns was successfully amplified and screened across populations with anorexia or bulimia nervosa, obsessive-compulsive disorder, autism, major depression and suicidality, impulsivity and alcoholism, and subjects enrolled in a tryptophan depletion study. There were no associations found for polymorphisms in introns 5, 6 or 11 nor for a variant in exon 7 (A to C, 749 Asn to His). In the SSCP screening of the promoter region no polymorphisms were found in the regions of two TATA boxes. An A to C variant was detected in the putative glucocorticoid site but was not associated with disease. However, in the promoter region of GTT repeats, a GTT insertion was found which may be associated with impulsivity and novelty seeking but not with alcoholism. The promoter region, exons 7 and 12, introns 5, 6, 11 and 12 and the UTR region are currently being screened by Denaturing High Performance Liquid Chromatography (DHPLC) to look for further polymorphisms and confirm those already found.
| Enoch, Mary-Anne (2003) Pharmacogenomics of alcohol response and addiction. Am J Pharmacogenomics 3:217-32 |
