Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder

Variation in genes involved in serotonergic signaling is thought to be associated with antidepressant treatment response in generalized anxiety disorder (GAD). We examined a possible interaction between the serotonin transporter gene (SLC6A4) 5-HTTLPR/rs25531 haplotype and the serotonin 2A receptor gene (HTR2A) single-nucleotide polymorphism (SNP) rs7997012 in antidepressant treatment outcome in GAD. Patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes obtained for the 5-HTTLPR/rs25531 (La/La, La/S or S/S) haplotype and rs7997012 SNP (G or A) in the European American population (n 112) were used for pharmacogenetic analysis. Our data show that subjects with genotypes La/La_G/G or La/La_G/A (n 28) had significantly lower Hamilton Anxiety Scale (HAM-A) scores than those with genotypes La/S_A/A or S/S_A/A (n 12) at 6 months (HAM-A difference 10.7; Po0.0001). Single-marker analysis only showed HAM-A differences of 4.3 (5-HTTLPR/rs25531: La/La versus La/S_S/S) and 4.8 (rs7997012: G/G_G/A versus A/A), showing for the first time a significant gene-gene interaction between these markers.