TPH2 and TPH1: association of variants and interactions with heroin addiction.

The tryptophan hydroxylase 2 gene (TPH2) was resequenced at the 5' upstream, coding, and 3' downstream regions, including all 11 exons in 185 subjects. Twenty-three novel and 14 known variants were identified. In a cohort of 583 consecutively ascertained subjects, including normal volunteers and those with specific addictive diseases, six common TPH2 and one TPH1 variant were genotyped. Allele frequencies of three TPH2 variants and the TPH1 variant varied significantly among the four ethnic groups within the control subjects. Of these subjects, 385 who met heroin addiction or control criteria and were of Caucasian, African-American, or Hispanic ethnicity were examined for potential association with vulnerability to develop heroin addiction. At the two locus genotype level in Hispanics, the TPH1 rs1799913 variant was found to significantly interact with the TPH2 rs7963720 variant and heroin addiction (P=0.022), and with the TPH2 rs4290270 variant and heroin addiction (P=0.011). In the African-American group, a significant association of a specific TPH2 haplotype with heroin addiction also was found (SNPHAP, P=0.004; PHASE P=0.036).