AbstractBackground:Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.Methods:41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.Results:Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).Conclusions:These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.