Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.

BACKGROUND: Phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) are the two key enzymes in the metabolism of polyunsaturated fatty acids, which in turn play an important role in cytokine-induced depression and sickness behavior. METHODS: Patients with chronic hepatitis C viral infection (n = 132) were assessed to examine the effects of seven single nucleotide polymorphisms in COX2 and PLA2 genes on the development of depression during interferon (IFN)-alpha treatment; a subsample (n = 63) was assessed for the erythrocyte levels of the three main polyunsaturated fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid. An independent "replication" sample of patients with major depression unrelated to cytokine treatment (n = 82) was also examined. RESULTS: Twenty-eight percent of participants developed INF-alpha-induced depression. Participants with the PLA2 BanI GG or the COX2 rs4648308 AG genotypes had a higher risk of IFN-alpha-induced depression (odds ratio = 3.1 and 3.5, respectively). The "at risk" PLA2 genotype was associated with lower EPA levels, and the "at risk" COX2 genotype was associated with lower DHA levels, during IFN-alpha treatment. The PLA2 BanI GG polymorphism was also associated with more somatic symptoms of depression, both in patients with INF-alpha-induced depression and in the replication sample of patients with major depression. CONCLUSIONS: Genetic variations in the COX2 and PLA2 genes increase the risk of IFN-alpha-induced depression, possibly by affecting the levels of EPA and DHA. Moreover, PLA2 genotype is associated with somatic symptoms in depression. Our study confirms the role of inflammatory mechanisms in major depression.